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Animal viruses have their genetic material copied by a host cell after which they are released into the environment to cause disease.
Learning Objectives
• Describe various animal viruses and the diseases they cause
Key Points
• Animal viruses may enter a host cell by either receptor -mediated endocytosis or by changing shape and entering the cell through the cell membrane.
• Viruses cause diseases in humans and other animals; they often have to run their course before symptoms disappear.
• Examples of viral animal diseases include hepatitis C, chicken pox, and shingles.
Key Terms
• receptor-mediated endocytosis: a process by which cells internalize molecules (endocytosis) by the inward budding of plasma membrane vesicles containing proteins with receptor sites specific to the molecules being internalized
Animal Viruses
Animal viruses, unlike the viruses of plants and bacteria, do not have to penetrate a cell wall to gain access to the host cell. Non-enveloped or “naked” animal viruses may enter cells in two different ways. When a protein in the viral capsid binds to its receptor on the host cell, the virus may be taken inside the cell via a vesicle during the normal cell process of receptor-mediated endocytosis. An alternative method of cell penetration used by non-enveloped viruses is for capsid proteins to undergo shape changes after binding to the receptor, creating channels in the host cell membrane. The viral genome is then “injected” into the host cell through these channels in a manner analogous to that used by many bacteriophages. Enveloped viruses also have two ways of entering cells after binding to their receptors: receptor-mediated endocytosis and fusion. Many enveloped viruses enter the cell by receptor-mediated endocytosis in a fashion similar to some non-enveloped viruses. On the other hand, fusion only occurs with enveloped virions. These viruses, which include HIV among others, use special fusion proteins in their envelopes to cause the envelope to fuse with the plasma membrane of the cell, thus releasing the genome and capsid of the virus into the cell cytoplasm.
After making their proteins and copying their genomes, animal viruses complete the assembly of new virions and exit the cell. Using the example of HIV, enveloped animal viruses may bud from the cell membrane as they assemble themselves, taking a piece of the cell’s plasma membrane in the process. On the other hand, non-enveloped viral progeny, such as rhinoviruses, accumulate in infected cells until there is a signal for lysis or apoptosis, and all virions are released together.
Animal viruses are associated with a variety of human diseases. Some of them follow the classic pattern of acute disease, where symptoms worsen for a short period followed by the elimination of the virus from the body by the immune system with eventual recovery from the infection. Examples of acute viral diseases are the common cold and influenza. Other viruses cause long-term chronic infections, such as the virus causing hepatitis C, whereas others, like herpes simplex virus, cause only intermittent symptoms. Still other viruses, such as human herpes viruses 6 and 7, which in some cases can cause the minor childhood disease roseola, often successfully cause productive infections without causing any symptoms at all in the host; these patients have an asymptomatic infection.
In hepatitis C infections, the virus grows and reproduces in liver cells, causing low levels of liver damage. The damage is so low that infected individuals are often unaware that they are infected, with many infections only detected by routine blood work on patients with risk factors such as intravenous drug use. Since many of the symptoms of viral diseases are caused by immune responses, a lack of symptoms is an indication of a weak immune response to the virus. This allows the virus to escape elimination by the immune system and persist in individuals for years, while continuing to produce low levels of progeny virions in what is known as a chronic viral disease. Chronic infection of the liver by this virus leads to a much greater chance of developing liver cancer, sometimes as much as 30 years after the initial infection.
As mentioned, herpes simplex virus can remain in a state of latency in nervous tissue for months, even years. As the virus “hides” in the tissue and makes few if any viral proteins, there is nothing for the immune response to act against; immunity to the virus slowly declines. Under certain conditions, including various types of physical and psychological stress, the latent herpes simplex virus may be reactivated and undergo a lytic replication cycle in the skin, causing the lesions associated with the disease. Once virions are produced in the skin and viral proteins are synthesized, the immune response is again stimulated and resolves the skin lesions in a few days by destroying viruses in the skin. As a result of this type of replicative cycle, appearances of cold sores and genital herpes outbreaks only occur intermittently, even though the viruses remain in the nervous tissue for life. Latent infections are common with other herpes viruses as well, including the varicella-zoster virus that causes chickenpox. After having a chickenpox infection in childhood, the varicella-zoster virus can remain latent for many years and reactivate in adults to cause the painful condition known as “shingles”. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.05%3A_Viral_Replication/9.5D%3A_Animal_Viruses.txt |
Plant viruses are often spread from plant to plant by organisms known as vectors.
Learning Objectives
• Outline plant virus life cycles
Key Points
• Plant viruses are harmless to humans and other animals because they can only reproduce in living plant cells.
• For the virus to reproduce and thereby establish infection, it must enter cells of the host organism and use those cells’ materials.
• A virus must take control of the host cell’s replication mechanisms. At this stage a distinction between susceptibility and permissibility of a host cell is made.
• After control is established and the environment is set for the virus to begin making copies of itself, replication occurs quickly by the millions.
Key Terms
• vector: A carrier of a disease-causing agent.
Plant viruses are viruses that affect plants. Like all other viruses, plant viruses are obligate intracellular parasites that do not have the molecular machinery to replicate without a host. Plant viruses are pathogenic to higher plants.
There are many types of plant virus, but often they only cause a loss of yield, and it is not economically viable to try to control them. Plant viruses are often spread from plant to plant by organisms ( vectors ). These are normally insects, but some fungi, nematode worms and single-celled organisms have been shown to be vectors. When control of plant virus infections is considered economical, (for perennial fruits for example), efforts are concentrated on killing the vectors and removing alternate hosts such as weeds. Plant viruses are harmless to humans and other animals because they can only reproduce in living plant cells.
Viral Life Cycle
For the virus to reproduce and thereby establish infection, it must enter cells of the host organism and use those cells’ materials. To enter the cells, proteins on the surface of the virus interact with proteins of the cell. Attachment, or adsorption, occurs between the viral particle and the host cell membrane. A hole forms in the cell membrane, then the virus particle or its genetic contents are released into the host cell, where viral reproduction may commence. Next, a virus must take control of the host cell’s replication mechanisms. At this stage, a distinction between susceptibility and permissibility of a host cell is made. Permissibility determines the outcome of the infection. After control is established and the environment is set for the virus to begin making copies of itself, replication occurs quickly by the millions. After a virus has made many copies of itself, it usually has exhausted the cell of its resources. The host cell is now no longer useful to the virus, therefore the cell often dies and the newly produced viruses must find a new host. The process by which virus progeny are released to find new hosts, is called shedding. This is the final stage in the viral life cycle. Some viruses can “hide” within a cell, either to evade the host cell defenses or immune system, or simply because it is not in the best interest of the virus to continually replicate. This hiding is deemed latency. During this time, the virus does not produce any progeny, it remains inactive until external stimuli—such as light or stress—prompts it to activate.
Viruses can be spread by direct transfer of sap, and by contact of a wounded plant with a healthy one. Such contact may occur during agricultural practices, when damage is caused by tools or hands, or naturally, when an animal feeds on the plant. Generally Tobacco mosaic virus (TMV), potato viruses, and cucumber mosaic viruses are transmitted via sap.
Tobacco mosaic virus and Cauliflower mosaic virus (CaMV) are frequently used in plant molecular biology. Of special interest is the CaMV 35S promoter, which is a very strong promoter most frequently used in plant transformations.
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Learning Objectives
• Distinguish between defective viruses, satellite viruses, and helper viruses
Virologists also study subviral particles, infectious entities notably smaller and simpler than viruses:
• viroids (naked circular RNA molecules infecting plants)
• satellites (nucleic acid molecules with or without a capsid that require a helper virus for infection and reproduction)
• prions (proteins that can exist in a pathological conformation that induces other prion molecules to assume that same conformation)
Not all viruses can reproduce in a host cell by themselves. Since viruses are so small, the size of their genome is limited. For example, some viruses have coded instructions for only making a few different proteins for the viruses’ capsid. On the other hand, the human genome codes for over 30,000 different proteins. Therefore, the lack of coded instructions causes some viruses to need the presence of other viruses to help them reproduce themselves. Such viruses are called replication defective.
Satellites depend on co-infection of a host cell with a helper virus for productive multiplication. Their nucleic acids have substantially distinct nucleotide sequences from either their helper virus or host. When a satellite subviral agent encodes the coat protein in which it is encapsulated, it is then called a satellite virus. Satellite viral particles should not be confused with satellite DNA.
The hepatitis delta virus of humans has an RNA genome similar to viroids, but has a protein coat derived from hepatitis B virus and cannot produce one of its own. Therefore, it is a defective virus and cannot replicate without the help of hepatitis B virus. In similar manner, the sputnik virophage is dependent on mimivirus, which infects the protozoan Acanthamoeba castellanii. These viruses that are dependent on the presence of other virus species in the host cell are called satellites. They may represent evolutionary intermediates of viroids and viruses.
Hepatitis D, also referred to as hepatitis D virus (HDV) and classified as Hepatitis delta virus, is a disease caused by a small circular enveloped RNA virus. It is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a subviral satellite because it can only propagate in the presence of the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection). Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased chance of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections of 20%.
Key Points
• Not all viruses can reproduce in a host cell by themselves. Since viruses are so small, the size of their genome is limited. The lack of coded instructions causes some viruses to need the presence of other viruses to help them reproduce themselves. Such viruses are called replication defective.
• A satellite is a subviral agent composed of nucleic acid that depends on the co- infection of a host cell with a helper or master virus for its multiplication. When a satellite encodes the coat protein in which its nucleic acid is encapsidated it is referred to as a satellite virus.
• These viruses that are dependent on the presence of other virus species in the host cell are called satellites and may represent evolutionary intermediates of viroids and viruses.
Key Terms
• Helper virus: A helper virus is a virus used when producing copies of a helper dependent viral vector which does not have the ability to replicate on its own. The helper virus is used to coinfect cells alongside the viral vector and provides the necessary enzymes for replication of the genome of the viral vector.
• Satellite: A subviral agent composed of nucleic acid that depends on the co-infection of a host cell with a helper or master virus for its multiplication. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.06%3A_Subviral_Entities/9.6A%3A_Defective_Viruses.txt |
Learning Objectives
• Relate the structure and replication of a viroid to its ability to cause diseases in plants
Viroids are plant pathogens that consist of a short stretch (a few hundred nucleobases) of highly complementary, circular, single-stranded RNA without the protein coat that is typical for viruses. In comparison, the genome of the smallest known viruses capable of causing an infection by themselves is around 2 kilobases in size. The human pathogen Hepatitis D virus is similar to viroids. Viroids are extremely small in size, ranging from 246 to 467 nucleotide (nt) long genome and consisting of fewer than 10,000 atoms. Viroids were discovered and given this name by Theodor Otto Diener, a plant pathologist at the Agricultural Research Service in Maryland, in 1971.
Viroid RNA does not code for any protein. The replication mechanism involves RNA polymerase II, an enzyme normally associated with synthesis of messenger RNA from DNA, which instead catalyzes “rolling circle” synthesis of new RNA using the viroid’s RNA as template. Some viroids are ribozymes, having catalytic properties which allow self-cleavage and ligation of unit-size genomes from larger replication intermediates. The first viroid to be identified was the potato spindle tuber viroid (PSTVd). Some 33 species have been identified.
There has long been confusion over how viroids are able to induce symptoms in plants without encoding any protein products within their sequences. Evidence now suggests that RNA silencing is involved in the process. First, changes to the viroid genome can dramatically alter its virulence. This reflects the fact that any siRNAs produced would have less complementary base pairing with target messenger RNA. Secondly, siRNAs corresponding to sequences from viroid genomes have been isolated from infected plants. Finally, transgenic expression of the noninfectious hpRNA of potato spindle tuber viroid develops all the corresponding viroid like symptoms. This evidence indicates that when viroids replicate via a double stranded intermediate RNA, they are targeted by a dicer enzyme and cleaved into siRNAs that are then loaded onto the RNA-induced silencing complex. The viroid siRNAs actually contain sequences capable of complementary base pairing with the plant’s own messenger RNAs and induction of degradation or inhibition of translation is what causes the classic viroid symptoms.
Virusoids are circular single-stranded RNAs dependent on plant viruses for replication and encapsidation. The genome of virusoids consists of several hundred nucleotides and only encodes structural proteins. Virusoids are similar to viroids in size, structure, and means of replication. Virusoids, while being studied in virology, are not considered as viruses but as subviral particles. Since they depend on helper viruses, they are classified as satellites.
The Pospiviroidae are a family of viroids, including the first viroid to be discovered, PSTVd. Their secondary structure is key to their biological activity. The classification of this family is based on differences in the conserved central region sequence. Pospiviroidae replication occurs in an asymmetric fashion via host cell RNA polymerase, RNase, and RNA ligase.
The Avsunviroidae are a family of viroids. At present three members are known. They consist of RNA genomes between 246-375 nucleotides in length. They are single stranded covalent circles and have intramolecular base pairing. All members lack a central conserved region. Replication occurs in the chloroplasts of plant cells. Key features of replication include no helper virus required and no proteins are encoded for. Unlike the other family of viroids, Pospiviroidae, Avsunviroidae are thought to replicate via a symmetrical rolling mechanism. It is thought the positive RNA strand acts as a template to form negative strands with the help of an enzyme thought to be RNA polymerase II. The negative RNA strands are then cleaved by ribozyme activity and circularizes. A second rolling circle mechanism forms a positive strand which is also cleaved by ribozyme activity and then ligated to become circular. The site of replication is unknown, but it is thought to be in the chloroplast and in the presence of Mg2+ ions.
Avocado sunblotch viroid (ASBV) is an important disease affecting avocado trees. Infections result in lower yields and poorer quality fruit. ASBV is the smallest known viroid that infects plants and is transmitted by pollen and infected seeds or budwood. Trees infected with the viroid often show no symptoms other than a reduction in yield. However, they are still carriers and can pass the disease onto other plants. Symptoms in more serious infections include depressed longitudinal streaks of yellow in the fruit. The fruit may also become red or white in color. Symptoms in the leaf are uncommon, but include bleached veins and petioles. Rectangular cracking patterns also occur in the bark of older branches. Infected but symptomless trees have a higher concentration of viroid particles than those showing symptoms. Symptomless trees also represent a greater danger in terms of spread of the viroid.
Key Points
• Viroid RNA does not code for any protein. The replication mechanism involves RNA polymerase II, an enzyme normally associated with synthesis of messenger RNA from DNA, which instead catalyzes “rolling circle” synthesis of new RNA using the viroid’s RNA as template.
• The first viroid to be identified was potato spindle tuber viroid (PSTVd). Some 33 species have been identified.
• There has long been confusion over how viroids are able to induce symptoms in plants without encoding any protein products within their sequences. Evidence now suggests that RNA silencing is involved in the process.
• Virusoids are circular single-stranded RNAs dependent on plant viruses for replication and encapsidation. Since they depend on helper viruses, they are classified as satellites.
Key Terms
• Virusoid: Circular single-stranded RNAs dependent on plant viruses for replication and encapsidation. The genome of virusoids consist of several hundred nucleotides and only encodes structural proteins.
• viroid: plant pathogens, of the order Viroidales, that consist of just a short section of RNA but without the protein coat typical of viruses | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.06%3A_Subviral_Entities/9.6B%3A_Viroids.txt |
Learning Objectives
• Compare the protein-only hypothesis of prion diseases with the virion hypothesis, as well as the heterodimer model and the fibril model of prion replication
A prion is an infectious agent composed of protein in a misfolded form. This is the central idea of the Prion Hypothesis, which remains debated. This is in contrast to all other known infectious agents (virus /bacteria/fungus/parasite) which must contain nucleic acids (either DNA, RNA, or both). The word prion, coined in 1982 by Stanley B. Prusiner, is derived from the words protein and infection. Prions are responsible for the transmissible spongiform encephalopathies in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as “mad cow disease”) in cattle and Creutzfeldt–Jakob disease (CJD) in humans. All known prion diseases affect the structure of the brain or other neural tissue, are currently untreatable and universally fatal.
Prions propagate by transmitting a misfolded protein state. When a prion enters a healthy organism, it induces existing, properly folded proteins to convert into the disease-associated prion form; it acts as a template to guide the misfolding of more proteins into prion form. These newly-formed prions can then go on to convert more proteins themselves; triggering a chain reaction. All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly-packed beta sheets. Amyloid aggregates are fibrils, growing at their ends, and replicating when breakage causes two growing ends to become four growing ends.
The incubation period of prion diseases is determined by the exponential growth rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates. Propagation of the prion depends on the presence of normally-folded protein in which the prion can induce misfolding; animals which do not express the normal form of the prion protein cannot develop nor transmit the disease.
All known mammalian prion diseases are caused by the so-called prion protein, PrP. The endogenous, properly-folded form is denoted PrPC (for Common or Cellular) while the disease-linked, misfolded form is denoted PrPSc (for Scrapie, after one of the diseases first linked to prions and neurodegeneration. ) The precise structure of the prion is not known, though they can be formed by combining PrPC, polyadenylic acid, and lipids in a Protein Misfolding Cyclic Amplification (PMCA) reaction.
Proteins showing prion-type behavior are also found in some fungi, which has been useful in helping to understand mammalian prions. Fungal prions do not appear to cause disease in their hosts.
The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer model. This model assumed that a single PrPSc molecule binds to a single PrPC molecule and catalyzes its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare. Manfred Eigen showed that the heterodimer model requires PrPSc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 1015. This problem does not arise if PrPSc exists only in aggregated forms such as amyloid, where cooperativity may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrPSc has never been isolated.
An alternative model assumes that PrPSc exists only as fibrils, and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linearly, forming ever longer fibrils. But exponential growth of both PrPSc and of the quantity of infectious particles is observed during prion disease. This can be explained by taking into account fibril breakage. A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found.
The protein-only hypothesis has been criticised by those who feel that the simplest explanation of the evidence to date is viral. For more than a decade, Yale University neuropathologist Laura Manuelidis has been proposing that prion diseases are caused instead by an unidentified slow virus. In January 2007, she and her colleagues published an article reporting to have found a virus in 10%, or less, of their scrapie-infected cells in culture.
The virion hypothesis states that TSEs are caused by a replicable informational molecule (likely to be a nucleic acid) bound to PrP. Many TSEs, including scrapie and BSE, show strains with specific and distinct biological properties, a feature which supporters of the virion hypothesis feel is not explained by prions.
Recent studies propagating TSE infectivity in cell-free reactions and in purified component chemical reactions strongly suggest against TSE’s viral nature. Using a similar defined recipe of multiple components (PrP, POPG lipid, RNA), Jiyan Ma and colleagues generated infectious prions from recombinant PrP expressed from E. coli, casting further doubt on this hypothesis.
Key Points
• Prions are responsible for the transmissible spongiform encephalopathies in a variety of mammals, including bovine spongiform encephalopathy and Creutzfeldt–Jakob disease in humans. All known prion diseases affect the structure of neural tissue, are currently untreatable and universally fatal.
• Prions propagate by transmitting a misfolded protein state. When a prion enters a healthy organism, it induces existing, properly-folded proteins to convert into the disease-associated, prion form; it then acts as a template to guide the misfolding of more proteins into prion form.
• All known mammalian prion diseases are caused by the so-called prion protein, PrP. The endogenous, properly folded, form is denoted PrPC while the disease-linked, misfolded form is denoted PrPSc.The precise structure of the prion is not known.
• The first hypothesis to explain how prions replicate in a protein-only manner was the heterodimer model, which assumed that a single PrPSc molecule binds to a single PrPC molecule and catalyzes its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC.
• An alternative model assumes that PrPSc exists only as fibrils and that fibril ends bind PrPC and convert it into PrPSc. The exponential growth of both PrPSc and of the quantity of infectious particles observed during prion disease can be explained by taking fibril breakage into account.
• The protein-only hypothesis has been criticised by those who feel that the simplest explanation of the evidence to date is viral. However, recent studies propagating TSE infectivity in cell-free reactions and in purified component chemical reactions strongly suggest against TSE’s viral nature.
Key Terms
• Amyloid: Insoluble fibrous protein aggregates sharing specific structural traits. They arise from at least 18 inappropriately folded versions of proteins and polypeptides present naturally in the body. These misfolded structures alter their proper configuration such that they erroneously interact with one another or other cell components forming insoluble fibrils. They have been associated with the pathology of more than 20 serious human diseases in that, abnormal accumulation of amyloid fibrils in organs may lead to amyloidosis, and may play a role in various neurodegenerative disorders.
• Creutzfeldt–Jakob disease: A degenerative neurological disorder (brain disease) that is incurable and invariably fatal. In CJD, the brain tissue develops holes and takes on a sponge-like texture, due to a type of infectious protein called a prion.
• prion: A self-propagating misfolded conformer of a protein that is responsible for a number of diseases that affect the brain and other neural tissue.
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Bacteriophages are viruses that infect bacteria and are among the most common and diverse entities in the biosphere.
Learning Objectives
• Evaluate the complexity of bacteriophages
Key Points
• Phages are obligate intracellular parasites that are able to reproduce only while infecting bacteria. Bacteriophages are comprised of proteins that encapsulate a DNA or RNA genome.
• Bacteriophages occur in over 140 bacterial or archaeal genera. They arose repeatedly in different hosts and there are at least 11 separate lines of descent. Nineteen families are currently recognised that infect bacteria and archaea.
• Phages are widely distributed in locations populated by bacterial hosts, such as soil or the intestines of animals. One of the densest natural sources for phages and other viruses is sea water.
• Bacteriophages may have a lytic cycle or a lysogenic cycle, and a few viruses are capable of carrying out both.
• To enter a host cell, bacteriophages attach to specific receptors on the surface of bacteria. This specificity means a bacteriophage can infect only certain bacteria bearing receptors to which they can bind, which in turn determines the phage’s host range.
Key Terms
• bacteriophage: A virus that specifically infects bacteria.
• lysogeny: the process by which a bacteriophage incorporates its nucleic acids into a host bacterium
Bacteriophages
Bacteriophages (phages) are potentially the most numerous “organisms” on Earth. They are among the most common and diverse entities in the biosphere. They are the viruses of bacteria (more generally, of prokaryotes). Phages are obligate intracellular parasites, meaning that they are able to reproduce only while infecting bacteria. Bacteriophages are comprised of proteins that encapsulate a DNA or RNA genome, and may have relatively simple or elaborate structures. Their genomes may encode as few as four genes, and as many as hundreds of genes. Phages replicate within bacteria following the injection of their genome into the cytoplasm.
Phage-ecological interactions are quantitatively vast. Bacteria (along with archaea) are highly diverse, with possibly millions of species. Phage-ecological interactions are also qualitatively diverse. There are huge numbers of environment types, bacterial-host types, and also individual phage types. Bacteriophages occur in over 140 bacterial or archaeal genera. They arose repeatedly in different hosts and there are at least 11 separate lines of descent. Over 5100 bacteriophages have been examined in the electron microscope since 1959. Of these, at least 4950 phages (96%) have tails. Of the tailed phages 61% have long, noncontractile tails (Siphoviridae). Tailed phages appear to be monophyletic and are the oldest known virus group.
Phages are widely distributed in locations populated by bacterial hosts, such as soil or the intestines of animals. One of the densest natural sources for phages and other viruses is sea water, where up to 9×108 virions per milliliter have been found in microbial mats at the surface. Up to 70% of marine bacteria may be infected by phages.
The dsDNA tailed phages, or Caudovirales, account for 95% of all the phages reported in the scientific literature, and possibly make up the majority of phages on the planet. However, other phages occur abundantly in the biosphere, with different virions, genomes and lifestyles. Phages are classified by the International Committee on Taxonomy of Viruses (ICTV) according to morphology and nucleic acid.
Nineteen families are currently recognised that infect bacteria and archaea. Of these, only two families have RNA genomes and only five families are enveloped. Of the viral families with DNA genomes, only two have single-stranded genomes. Eight of the viral families with DNA genomes have circular genomes, while nine have linear genomes. Nine families infect bacteria only, nine infect archaea only, and one (Tectiviridae) infects both bacteria and archaea.
Bacteriophages may have a lytic cycle or a lysogenic cycle, and a few viruses are capable of carrying out both. With lytic phages such as the T4 phage, bacterial cells are broken open (lysed) and destroyed after immediate replication of the virion. As soon as the cell is destroyed, the phage progeny can find new hosts to infect.
In contrast, the lysogenic cycle does not result in immediate lysing of the host cell. Those phages able to undergo lysogeny are known as temperate phages. Their viral genome will integrate with host DNA and replicate along with it fairly harmlessly, or may even become established as a plasmid. The virus remains dormant until host conditions deteriorate, perhaps due to depletion of nutrients; then, the endogenous phages (known as prophages) become active. At this point they initiate the reproductive cycle, resulting in lysis of the host cell. As the lysogenic cycle allows the host cell to continue to survive and reproduce, the virus is reproduced in all of the cell’s offspring. An example of a bacteriophage known to follow the lysogenic cycle and the lytic cycle is the phage lambda of E. coli.
To enter a host cell, bacteriophages attach to specific receptors on the surface of bacteria, including lipopolysaccharides, teichoic acids, proteins, or even flagella. This specificity means a bacteriophage can infect only certain bacteria bearing receptors to which they can bind, which in turn determines the phage’s host range. Host growth conditions also influence the ability of the phage to attach and invade them.
Phages may be released via cell lysis, by extrusion, or, in a few cases, by budding. Lysis, by tailed phages, is achieved by an enzyme called endolysin, which attacks and breaks down the cell wall peptidoglycan. An altogether different phage type, the filamentous phages, make the host cell continually secrete new virus particles. Budding is associated with certain Mycoplasma phages.
Bacteriophage genomes are especially mosaic: the genome of any one phage species appears to be composed of numerous individual modules. These modules may be found in other phage species in different arrangements. Mycobacteriophages – bacteriophages with mycobacterial hosts – have provided excellent examples of this mosaicism. In these mycobacteriophages, genetic assortment may be the result of repeated instances of site-specific recombination and illegitimate recombination (the result of phage genome acquisition of bacterial host genetic sequences). | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.07%3A_Viral_Diversity/9.7A%3A_Overview_of_Bacterial_Viruses.txt |
Nineteen families of bacteriophages that infect bacteria and archaea are currently recognized; of these, only two families have RNA genomes.
Learning Objectives
• Identify differences between bacterial ssRNA and dsRNA viruses
Key Points
• Cystovirus is a genus of dsRNA virus that infect certain Gram-negative bacteria. All cystoviruses are distinguished by their three strands of dsRNA and their protein and lipid outer layer. No other bacteriophage has any lipid in its outer coat.
• RNA -dependent RNA polymerases (RdRPs) are critical components in the life cycle of double-stranded RNA (dsRNA) viruses. However, it is not fully understood how these important enzymes function during viral replication.
• Bacteriophage Φ6 is a member of the Cystoviridae family that infects Pseudomonas bacteria (typically plant-pathogenic P. syringae). It is a lytic phage, though under certain circumstances has been observed to display a delay in lysis that may be described as a “carrier state”.
Key Terms
• RNA genome: Like DNA, RNA can carry genetic information. RNA viruses have genomes composed of RNA that encodes a number of proteins.
Nineteen families of bacteriophages that infect bacteria and archaea are currently recognized. Of these, only two families have RNA genomes: Cystoviridae (segmented dsRNA) and Leviviridae (linear ssRNA).
The Leviviridae include the genera Allolevivirus (type species: Enterobacteria phage Qβ) and Levivirus (type species: Enterobacteria phage MS2).
Cystovirus is a genus of dsRNA virus that infect certain Gram-negative bacteria. All cystoviruses are distinguished by their three strands (analogous to chromosomes) of dsRNA, totalling ~14 kb in length, and by their protein and lipid outer layer. No other bacteriophage has any lipid in its outer coat, though the Tectiviridae and the Corticoviridae have lipids within their capsids.
Most identified cystoviruses infect Pseudomonas species, but this is likely biased due to the method of screening and enrichment. The type species is Pseudomonas phage Φ6, but there are many other members of this family: Φ7, Φ8, Φ9, Φ10, Φ11, Φ12, and Φ13 have been identified and named, but other cystoviruses have also been isolated.
Members of the Cystoviridae appear to be most closely related to the Reoviridae, but also share homology with the Totiviridae. Cystoviruses are the only bacteriophage that are more closely related to viruses of eukaryotes than to other phage.
Bacteriophage Φ6 is a member of the Cystoviridae family. It infects Pseudomonas bacteria (typically plant-pathogenic P. syringae). It has a three-part, segmented, double-stranded RNA genome, totalling ~13.5 kb in length. Φ6 and its relatives have a lipid membrane around their nucleocapsid, a rare trait among bacteriophages. It is a lytic phage, though under certain circumstances has been observed to display a delay in lysis that may be described as a “carrier state. ”
Φ6 typically attaches to the Type IV pilus of P. syringae with its attachment protein, P3. It is thought that the cell then retracts its pilus, pulling the phage toward the bacterium. Fusion of the viral envelope with the bacterial outer membrane is facilitated by the phage protein, P6. The muralytic (peptidoglycan-digesting) enzyme, P5, then digests a portion of the cell wall, and the nucleocapsid enters the cell coated with the bacterial outer membrane.
RNA-dependent RNA polymerases (RdRPs) are critical components in the life cycle of double-stranded RNA (dsRNA) viruses. However, it is not fully understood how these important enzymes function during viral replication. Expression and characterization of the purified recombinant RdRP of Φ6 is the first direct demonstration of RdRP activity catalyzed by a single protein from a dsRNA virus. The recombinant Φ6 RdRP is highly active in vitro, possesses RNA replication and transcription activities, and is capable of using both homologous and heterologous RNA molecules as templates. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.07%3A_Viral_Diversity/9.7B%3A_RNA_Bacteriophages.txt |
Of the viral families with DNA genomes, only two have single-stranded genomes, the Inoviridae and the Microviridae.
Learning Objectives
• Illustrate the characteristics and life cycle of ssDNA bacteriophages
Key Points
• The Inoviridae are a family of filamentous bacteriophages. The virons are non-enveloped, rod-shaped, and filamentous. Viron release may involve host lysis, but alternatively productive infection may occur by budding from the host membrane.
• The Microviridae are a family of bacteriophages with a single-stranded DNA genome. Their genomes are among the smallest of the DNA viruses. Although the majority of species in this family have lytic life cycles, a few may have temperate life cycles.
• The Microviridae are divided into two subfamilies, Gokushovirinae and Microvirinae. These groups differ in their hosts, genome structure, and viron composition.
Key Terms
• microviridae: The Microviridae are a family of bacteriophages with a single-stranded DNA genome.
• virion: A single individual particle of a virus (the viral equivalent of a cell).
Nineteen viral families are currently recognized that infect bacteria and archaea. Of these, only two families have RNA genomes and only five are enveloped. Of the viral families with DNA genomes, only two have single-stranded genomes.
Inoviridae
The Inoviridae are a family of filamentous bacteriophages. The name of the family is derived from the Greek nos, meaning “muscle. ”
Taxonomy
There are two genera in this family: Inovirus and Plectrovirus. These genera differ in their host range: Plectovirii infect hosts of the class Mollicutes, while Inovirii infect species of the Enterobacteriaceae, Pseudomonadaceae, Spirillaceae, Xanthomonadaceae, Clostridium, and Propionibacterium classes.
Physical and Genomic Properties
Inoviridae are non-enveloped, rod-shaped, and filamentous. The capsid has a helical symmetry, and in general has a length of 85-280 nm or 760-1950 nm and a width of 10-16 nm or 6-8 nm, respectively. These morphological differences depend on the species.
The genomes are non-segmented, circular, positive-sense, single-stranded DNA, 4.4-8.5 kilobases in length. They encode 4 to 11 proteins. Replication of the genome occurs via a dsDNA intermediate and the rolling circle mechanism. Gene transcription is by the host’s cellular machinery, as each gene has a specific promoter.
Life Cycle
There are six steps in the life cycle of Inoviridae:
1. Adsorbion to the host via specific receptor(s)
2. Movement of the viral DNA into the host cell
3. Conversion of the single-strand form to a double-stranded intermediate
4. Replication of the viral genome
5. Synthesis of the new virions
6. Release of the new virions from the host
Action in Host
Conversion from single-stranded to double-stranded form is carried out by the host’s own DNA polymerase. The host’s RNA polymerase binds to the viral genome and syntheses RNA. Some of this RNA is translated and the remainder is used to initiate DNA replication.
Virion release may involve host lysis, but alternatively productive infection may occur by budding from the host membrane. This pattern is typically seen in the Plectivirus genus. A number of exceptions to this life cycle are known. Lysogenic species, which encode integrases, exist within this family.
Microviridae
The Microviridae are a family of bacteriophages with a single-stranded DNA genome. The name of this family is derived from the Greek micro, meaning “small. ” This refers to the size of their genomes, which are among the smallest of the DNA viruses.
Taxonomy
This family is divided into two subfamilies, Gokushovirinae (derived from the Japanese for “very small”) and Microvirinae. These groups differ in their hosts, genome structure, and virion composition.
Gokushoviruses are currently known to infect only obligate intra-cellular parasites. These species are members of the genera Bdellovibrio, Chlamydia, and Spiroplasma. Subfamily Microvirinae are all of the genus Microvirus. All seven such members infect Enterobacteria.
Physical and Genomic Properties
Members of the subfamily Gokushovirus have only two structural proteins: capsid proteins F (Virus Protein 1) and DNA pilot protein H (Virus Protein 2) and do not use scaffolding proteins. They also possess ‘mushroom-like’ protrusions positioned at the three-fold axes of symmetry of their icosahedral capsids. These are formed by large insertion loops within the protein F of gokushoviruses and are absent in the microviruses. They lack both the external scaffolding protein D and the major spike protein G of the species in the genus Microvirus. The genomes of this group tend to be smaller, about 4.5 kb in length. This subfamily includes the genera Bdellomicrovirus, Chlamydiamicrovirus, and Spiromicrovirus.
Microviridae are non-enveloped and round with an icosahedral symmetry. They have a diameter between 25-27 nanometers and lack tails. Each virion has 60 copies each of the F, G, and J proteins and 12 copies of the H protein. Viruses in this family replicate their genomes via a rolling circle mechanism and encode dedicated RCR initiation proteins. Although the majority of species in this family have lytic life cycles, a few may have temperate life cycles.
Life Cycle
There are a number of steps in the life cycle:
1. Adsorbion to the host via specific receptor(s)
2. Movement of the viral DNA into the host cell
3. Conversion of the single-strand form to a double-stranded intermediate, known as the replicative form I
4. Transcription of early genes
5. Replication of the viral genome
6. Late genes are now transcribed by the host’s RNA polymerase
7. Synthesis of the new virions
8. Maturation of the virions in the host cytoplasm
9. Release from the host
Action in Host
Cell lysis is mediated by the phiX174-encoded protein E, which inhibits the peptidoglycan synthesis, leading to the eventual bursting of the infected cell. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.07%3A_Viral_Diversity/9.7C%3A_Single-Stranded_DNA_Bacteriophages.txt |
The dsDNA tailed phages, or Caudovirales, account for 95% of all known phages and possibly make up the majority of phages on the planet.
Learning Objectives
• Describe dsDNA bacteriophages
Key Points
• The Caudovirales are an order of viruses also known as the tailed bacteriophages. The virus particles have a distinct shape; each virion has an icosohedral head that contains the viral genome, and is attached to a flexible tail by a connector protein.
• The order encompasses a wide range of viruses, many of which contain genes of similar nucleotide sequence and function. Some tailed bacteriophage genomes can vary quite significantly in nucleotide sequence, even among the same genus. There are at least 350 recognized species in this order.
• Because of the lack of homology between the amino acid and DNA sequences of these viruses, the three families here are defined based on morphology: the Myoviridae have long contractile tails, the Podoviridae have short noncontractile tails, and the Siphoviridae have long non-contractile tails.
Key Terms
• Caudovirales: A taxonomic order within the kingdom Virus—the bacteriophages that have tails.
The Double-Stranded DNA (dsDNA) tailed phages, or Caudovirales, account for 95% of all the phages reported in the scientific literature, and possibly make up the majority of phages on the planet. Nineteen families that infect bacteria and archaea are currently recognized; of these, 15 have double-stranded DNA genomes.
Under the Baltimore classification scheme, the Caudovirales are group I viruses as they have double-stranded DNA (dsDNA) genomes, which can be anywhere from 18,000 base pairs to 500,000 base pairs in length. The virus particles have a distinct shape; each virion has an icosohedral head that contains the viral genome, and is attached to a flexible tail by a connector protein. The order encompasses a wide range of viruses, many of which contain genes of similar nucleotide sequence and function. Some tailed bacteriophage genomes can vary quite significantly in nucleotide sequence, however, even among the same genus. Due to their characteristic structure and possession of potentially homologous genes, it is believed these bacteriophages possess a common origin. There are at least 350 recognized species in this order.
Upon encountering a host bacterium, the tail section of the virion binds to receptors on the cell surface and delivers the DNA into the cell by use of an injectisome-like mechanism (an injectisome is a nanomachine that evolved for the delivery of proteins by type III secretion). The tail section of the virus punches a hole through the bacterial cell wall and plasma membrane and the genome passes down the tail into the cell. Once inside, the genes are expressed from transcripts made by the host machinery, using host ribosomes. Typically, the genome is replicated by use of concatemers, in which overlapping segments of DNA are made, and then put together to form the whole genome.
Viral capsid proteins come together to form a precursor prohead, into which the genome enters. Once this has occurred, the prohead undergoes maturation by cleavage of capsid subunits to form an icosohedral phage head with 5-fold symmetry. After the head maturation, the tail is joined in one of two ways: either the tail is constructed separately and joined with the connector, or the tail is constructed directly onto the phage head. The tails consist of helix-based proteins with 6-fold symmetry. After maturation of virus particles, the cell is lysed by lysins, holins, or a combination of the two.
Because the lack of homology between the amino acid and DNA sequences of these viruses precludes these from being used as taxonomic markers (as is common for other organisms), the three families here are defined on the basis of morphology. This classification scheme was originated by Bradley in 1969 and has since been extended. All viruses in this order have icosahedral or oblate heads, but differ in the length and contractile abilities of their tails. The Myoviridae have long tails that are contractile, the Podoviridae have short noncontractile tails, and the Siphoviridae have long non-contractile tails. Siphoviridae constitute the majority of the known tailed viruses.
9.7E: Mu- A Double-Stranded Transposable DNA Bacteriophage
Bacteriophage Mu is a temperate bacteriophage that uses DNA-based transposition in its lysogenic cycle.
Learning Objectives
• Outline the life cycle of Mu phages
Key Points
• All of the known temperate phages employ one of only three different systems for their lysogenic cycle: lambda-like integration/excision, Mu-like transposition, or the plasmid-like partitioning of phage N15.
• Phage Mu uses DNA -based transposition to integrate its genome into the genome of the host cell that it is infecting. It can then use transposition to initiate its viral DNA replication.
• Mu phage transposition is the best-known example of replicative transposition. Its transposition mechanism is somewhat similar to a homologous recombination.
Key Terms
• replicative transposition: A mechanism of transposition in which the transposable element is duplicated during the reaction, so that the transposing entity is a copy of the original element.
Bacteriophage Mu, or phage Mu, is a temperate bacteriophage, a type of virus that infects bacteria. It belongs to the family Myoviridae, and consists of an icosahedral head, a contractile tail, and six tail fibers.
All of the known temperate phages employ one of only three different systems for their lysogenic cycle: lambda-like integration/excision, Mu-like transposition, or the plasmid-like partitioning of phage N15.
Mu bacteriophage uses DNA-based transposition to integrate its genome into the genome of the host cell that it is infecting. It can then use transposition to initiate its viral DNA replication. Once the viral DNA is inserted into the bacteria, the Mu’s transposase protein/enzyme in the cell recognizes the recombination sites at the ends of the viral DNA (gix-L and gix-R sites) and binds to them, allowing the process of replicating the viral DNA or embedding it into the host genome. A transposable element (TE) is a DNA sequence that can change its relative position (self-transpose) within the genome of a single cell. The mechanism of transposition can be either “copy and paste” or “cut and paste. ” Transposition can create phenotypically significant mutations and alter the cell’s genome size.
Mu phage transposition is the best known example of replicative transposition. Its transposition mechanism is somewhat similar to a homologous recombination. Replicative transposition is a mechanism of transposition in molecular biology, proposed by James A. Shapiro in 1979, in which the transposable element is duplicated during the reaction, so that the transposing entity is a copy of the original element. In this mechanism, the donor and receptor DNA sequences form a characteristic intermediate “theta” configuration, sometimes called a “Shapiro intermediate. ” Replicative transposition is characteristic to retrotransposons and occurs from time to time in class II transposons. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.07%3A_Viral_Diversity/9.7D%3A_Double-Stranded_DNA_Bacteriophages.txt |
T-4 bacteriophage is a virulent bacteriophage that infects E. coli bacteria; virulent bacteriophages have a lytic life cycle.
Learning Objectives
• Summarize how the T4 life cycle serves as a model for viral virulence
Key Points
• Virulence is the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism is determined by its virulence factors.
• A key difference between the lytic and lysogenic phage cycles is that in the lytic phage, the viral DNA exists as a separate molecule within the bacterial cell, and replicates separately from the host bacterial DNA.
• The T-4’s tail fibres allow attachment to a host cell, and the T4’s tail is hollow so that it can pass its nucleic acid to the cell it is infecting during attachment. T4 is capable of undergoing only a lytic lifecycle and not the lysogenic lifecycle.
Key Terms
• lytic cycle: The normal process of viral reproduction involving penetration of the cell membrane, nucleic acid synthesis, and lysis of the host cell.
• virulence: the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host.
Virulence is the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism is determined by its virulence factors. Virus virulence factors determine whether an infection will occur and how severe the resulting viral disease symptoms are. Viruses often require receptor proteins on host cells to which they specifically bind. Typically, these host cell proteins are endocytosed and the bound virus then enters the host cell. Virulent viruses such as HIV, which causes AIDS, have mechanisms for evading host defenses.
Some viral virulence factors confer ability to replicate during the defensive inflammation responses of the host such as during virus-induced fever. Many viruses can exist inside a host for long periods during which little damage is done. Extremely virulent strains can eventually evolve by mutation and natural selection within the virus population inside a host. The term “neurovirulent” is used for viruses such as rabies and herpes simplex which can invade the nervous system and cause disease there.
Model organisms of virulent viruses that have been extensively studied include virus T4 and other T-even bacteriophages which infect Escherichia coli and a number of related Bacteria.
The lytic cycle is one of the two cycles of viral reproduction, the other being the lysogenic cycle. The lytic cycle is typically considered the main method of viral replication, since it results in the destruction of the infected cell. A key difference between the lytic and lysogenic phage cycles is that in the lytic phage, the viral DNA exists as a separate molecule within the bacterial cell, and replicates separately from the host bacterial DNA. The location of viral DNA in the lysogenic phage cycle is within the host DNA, therefore in both cases the virus/phage replicates using the host DNA machinery, but in the lytic phage cycle, the phage is a free floating separate molecule to the host DNA.
The lytic cycle is a six-stage cycle. In the first stage, called “penetration,” the virus injects its own nucleic acids into a host cell. Then the viral acids form a circle in the center of the cell. The cell then mistakenly copies the viral acids instead of its own nucleic acids. Then the viral DNA organize themselves as viruses inside the cell. When the number of viruses inside becomes too much for the cell to hold, the membrane splits and the viruses are free to infect other cells. Some viruses escape the host cell without bursting the cell membrane; instead, they bud off from it by taking a portion of the membrane with them. Because it otherwise is characteristic of the lytic cycle in other steps, it still belongs to this category, although it is sometimes named the Productive Cycle. HIV, influenza and other viruses that infect eukaryotic organisms generally use this method.
T-4 bacteriophage is a bacteriophage that infects E. coli bacteria. Its double-stranded DNA genome is about 169 kbp long and is held in an icosahedral head, also known as a capsid. T4 is a relatively large phage, at approximately 90 nm wide and 200 nm long (most phages range from 25 to 200 nm in length). Its tail fibres allow attachment to a host cell, and the T4’s tail is hollow so that it can pass its nucleic acid to the cell it is infecting during attachment. T4 is capable of undergoing only a lytic lifecycle and not the lysogenic lifecycle.
The T4 Phage initiates an E. coli infection by recognizing cell surface receptors of the host with its long tail fibers (LTF). A recognition signal is sent through the LTFs to the baseplate. This unravels the short tail fibers (STF) that bind irreversibly to the E. coli cell surface. The baseplate changes conformation and the tail sheath contracts causing GP5 at the end of the tail tube to puncture the outer membrane of the cell. The lysozyme domain of GP5 is activated and degrades the periplasmic peptidoglycan layer. The remaining part of the membrane is degraded and then DNA from the head of the phage can travel through the tail tube and enter the E. coli.
The lytic lifecycle (from entering a bacterium to its destruction) takes approximately 30 minutes (at 37 °C) and consists of:
• Adsorption and penetration (starting immediately)
• Arrest of host gene expression (starting immediately)
• Enzyme synthesis (starting after 5 minutes)
• DNA replication (starting after 10 minutes)
• Formation of new virus particles (starting after 12 minutes)
After the life cycle is complete, the host cell bursts open and ejects the newly built viruses into the environment, destroying the host cell. T4 has a burst size of approximately 100-150 viral particles per infected host. Complementation, deletion, and recombination tests can be used to map out the rII gene locus by using T4. These bacteriophage infect a host cell with their information and then blow up the host cell, thereby propagating themselves.
The T4 phage has some unique features, including:
• Eukaryote-like introns
• High speed DNA copying mechanism, with only 1 error in 300 copies
• Special DNA repair mechanisms
• It infects E. coli O157:H7 | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.07%3A_Viral_Diversity/9.7F%3A_Virulent_Bacteriophages_and_T4.txt |
In virology, temperate refers to the ability of some bacteriophages to display a lysogenic life cycle.
Learning Objectives
• Evaluate the differences between the temperate phages, P1, and lambda
Key Points
• Many temperate phages can integrate their genomes into their host bacterium ‘s chromosome, together becoming a lysogen as the phage genome becomes a prophage. A temperate phage is also able to undergo a productive, typically-lytic life cycle.
• P1 is a temperate bacteriophage (phage) that infects Escherichia coli and some other bacteria. A unique feature of phage P1 is that during lysogeny its genome is not incorporated into the bacterial chromosome, as is commonly observed during lysogeny of other bacteriophage.
• Enterobacteria phage λ ( lambda phage, coliphage λ) is a bacterial virus, or bacteriophage, that infects the bacterial species Escherichia coli.
• With the infection of a bacteria by phage, a lytic cycle usually ensues where the lambda DNA is replicated many times and the genes for head, tail, and lysis proteins are expressed. Under certain conditions the phage DNA may integrate itself into the host cell chromosome in the lysogenic pathway.
Key Terms
• lytic life cycle: One of the two cycles of viral reproduction (the other being the lysogenic cycle). The lytic cycle is typically considered the main method of viral replication and it results in the destruction of the infected cell.
• temperate bacteriophage: Phages able to undergo lysogeny.
In virology, temperate refers to the ability of some bacteriophages (notable coliphage λ) to display a lysogenic life cycle. Many (but not all) temperate phages can integrate their genomes into their host bacterium’s chromosome, together becoming a lysogen as the phage genome becomes a prophage. A temperate phage is also able to undergo a productive, typically-lytic life cycle, where the prophage is expressed, replicates the phage genome, and produces phage progeny, which then leave the bacterium. With phage the term virulent is often used as an antonym to temperate, but more strictly a virulent phage is one that has lost its ability to display lysogeny through mutation, rather than a phage lineage with no genetic potential to ever display lysogeny (which more properly would be described as an obligately lytic phage).
P1 is a temperate bacteriophage (phage) that infects Escherichia coli and some other bacteria. When undergoing a lysogenic cycle, the phage genome exists as a plasmid in the bacterium, unlike other phages (e.g., the lambda phage) that integrate into the host DNA. P1 has an icosahedral “head” containing the DNA, attached to a contractile tail with six tail fibers.
The virion is similar in structure to the T4 phage, but simpler. It has an icosahedral head containing the genome attached at one vertex to the tail. The tail has a tube surrounded by a contractile sheath, and ends in a base plate with six tail fibers. The tail fibers are involved in attaching to the host and providing specificity.
At around 93Kbp in length, the genome of the P1 phage is moderately large compared to the genomes of others, like T4 (169Kbp), lambda (48Kbp), and Ff (6.4Kbp). In the viral particle it is in the form of a linear double-stranded DNA molecule. Once inserted into the host, it circularizes and replicates as a plasmid.
Temperate phage, such as P1, have the ability to exist within the bacterial cell they infect in two different ways. In lysogeny, P1 can exist within a bacterial cell as a circular DNA, in that it exists by replicating as if it were a plasmid and does not cause cell death. Alternatively, in its lytic phase, P1 can promote cell lysis during growth, resulting in host cell death. During lysogeny, new phage particles are not produced. In contrast, during lytic growth many new phage particles are assembled and released from the cell. By alternating between these two modes of infection, P1 can survive during extreme nutritional conditions that may be imposed upon the bacterial host in which it exists.
A unique feature of phage P1 is that during lysogeny its genome is not incorporated into the bacterial chromosome, as is commonly observed during lysogeny of other bacteriophage. Instead, P1 exists independently within the bacterial cell, much like a plasmid would. P1 replicates as a 90 kilobase (kb) plasmid in the lysogenic state and is partitioned equally into two new daughter cells during normal cell division.
Enterobacteria phage λ (lambda phage, coliphage λ) is a bacterial virus, or bacteriophage, that infects the bacterial species Escherichia coli. This virus is temperate and may reside within the genome of its host through lysogeny.
Lambda phage consists of a virus particle including a head (also known as a capsid), a tail, and tail fibers. The head contains the phage’s double-stranded circular DNA genome. The phage particle recognizes and binds to its host, E. coli, causing DNA in the head of the phage to be ejected through the tail into the cytoplasm of the bacterial cell. Usually, a “lytic cycle” ensues, where the lambda DNA is replicated many times and the genes for head, tail, and lysis proteins are expressed. This leads to assembly of multiple new phage particles within the cell and subsequent cell lysis, releasing the cell contents, including virions that have been assembled, into the environment. However, under certain conditions the phage DNA may integrate itself into the host cell chromosome in the lysogenic pathway. In this state, the λ DNA is called a prophage and stays resident within the host’s genome without apparent harm to the host. The host can be termed a lysogen when a prophage is present.
The virus particle consists of a head and a tail that can have tail fibers. The head contains 48,490 base pairs of double-stranded, linear DNA, with 12-base single-stranded segments at both 5′ ends. These two single-stranded segments are the “sticky ends” of what is called the cos site. The cos site circularizes the DNA in the host cytoplasm. In its circular form, the phage genome therefore is 48,502 base pairs in length. The prophage exists as a linear section of DNA inserted into the host chromosome. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.07%3A_Viral_Diversity/9.7G%3A_Temperate_Bacteriophages_-_Lambda_and_P1.txt |
Learning Objectives
• Illustrate the typical characteristics of archaea-infecting viruses
A virus infecting archaea was first described in 1974. Several others have been described since then. Most have head-tail morphologies and linear double-stranded DNA genomes. Other morphologies have also been described including spindle shaped, rod shaped, filamentous, icosahedral, and spherical. Additional morphological types may exist.
Archaea can be infected by double-stranded DNA viruses that are unrelated to any other form of virus and have a variety of unusual shapes. These viruses have been studied in the most detail in thermophilics, particularly the orders Sulfolobales and Thermoproteales. Two groups of single-stranded DNA viruses that infect archaea have been recently isolated. One group is exemplified by the Halorubrum pleomorphic virus 1 (“Pleolipoviridae”) infecting halophilic archaea and the other one by the Aeropyrum coil-shaped virus.
Double-stranded DNA viruses infecting archaea:
• Bacteriophages (viruses infecting bacteria) belonging to the families Tectiviridae and Corticoviridae have a lipid bilayer membrane inside the icosahedral protein capsid and the membrane surrounds the genome. The crenarchaeal virus Sulfolobus turreted icosahedral virus has a similar structure.
• Species of the order Ligamenvirales and the families Ampullaviridae, Bicaudaviridae, Clavaviridae, Fuselloviridae, Globuloviridae, and Guttaviridae infect hyperthermophilic archaea species of the Crenarchaeota.
• Species of the genus Salterprovirus infect halophilic archaea species of the Euryarchaeota.
Single-stranded DNA viruses infecting archaea:
Although around 50 archaeal viruses are known, all but two have double stranded genomes. The first archaeal ssDNA virus to be isolated is the Halorubrum pleomorphic virus 1, which has a pleomorphic enveloped virion and a circular genome. Defenses against these viruses may involve RNA interference from repetitive DNA sequences that are related to the genes of the viruses.
The second single stranded DNA virus infecting Archaea is Aeropyrum coil-shaped virus (ACV). The genome is circular and with 24,893 nucleotides is currently the largest known ssDNA genome. The viron is nonenveloped, hollow, cylindrical, and formed from a coiling fiber. The morphology and the genome appear to be unique. ACV has been suggested to represent a new viral family tentatively called “Spiraviridae” (from Latin spira, “a coil”). The Aeropyrum coil-shaped virus infects a hyperthermophilic (optimal growth at 90-95°C) host. Notably, the latter virus has the largest currently reported ssDNA genome.
Key Points
• Archaea can be infected by double-stranded DNA viruses that are unrelated to any other form of virus and have a variety of unusual shapes. These viruses have been studied in most detail in thermophilics, particularly the orders Sulfolobales and Thermoproteales.
• Although around 50 archaeal viruses are known, all but two have double stranded genomes; two groups of single-stranded DNA viruses that infect archaea have been recently isolated.
• Defenses against these ssDNA viruses may involve RNA interference from repetitive DNA sequences that are related to the genes of the viruses.
Key Terms
• DNA virus: A DNA virus is a virus that has DNA as its genetic material and replicates using a DNA-dependent DNA polymerase. The nucleic acid is usually double-stranded DNA (dsDNA) but may also be single-stranded DNA (ssDNA).
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Positive-Strand RNA Viruses of Animals
Positive strand RNA viruses are the single largest group of RNA viruses with 30 families.
LEARNING OBJECTIVES
Categorize the characteristics of positive-strand viruses
Key Points
• Nucleic acid is usually single-stranded RNA (ssRNA), but may be double-stranded RNA (dsRNA).
• An RNA virus is a virus that has RNA (ribonucleic acid) as its genetic material.
• Notable human diseases caused by RNA viruses include SARS, influenza, hepatitis C, West Nile fever, and polio.
Key Terms
• virus: A submicroscopic infectious organism, now understood to be a non-cellular structure consisting of a core of DNA or RNA surrounded by a protein coat. It requires a living cell to replicate, and often causes disease in the host organism.
• genetic: Relating to genetics or genes.
• RNA: Ribonucleic acid (RNA) is a ubiquitous family of large biological molecules that performs multiple vital roles in the coding, decoding, regulation, and expression of genes.
Single stranded RNA viruses can be classified according to the sense or polarity of their RNA into negative-sense and positive-sense, or ambisense RNA viruses. Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation. As such, purified RNA of a positive-sense virus can directly cause infection though it may be less infectious than the whole virus particle. Purified RNA of a negative-sense virus is not infectious by itself as it needs to be transcribed into positive-sense RNA; each virion can be transcribed to several positive-sense RNAs. Ambisense RNA viruses resemble negative-sense RNA viruses, except they also translate genes from the positive strand. A common viral positive-strand RNA viruses that infect humans are the picornaviruses.
A picornavirus is a virus belonging to the family Picornaviridae. Picornaviruses are non-enveloped, positive-stranded RNA viruses with an icosahedral capsid. The genome RNA is unusual because it has a protein on the 5′ end that is used as a primer for transcription by RNA polymerase. The name is derived from pico, meaning small, and RNA, referring to the ribonucleic acid genome, so “picornavirus” literally means small RNA virus. Picornaviruses are separated into a number of genera and include many important pathogens of humans and animals. The diseases they cause are varied, ranging from acute “common-cold”-like illnesses, to poliomyelitis, to chronic infections in livestock. Additional species not belonging to any of the recognized genera continue to be described.
Picornaviruses are separated into a number of genera. Contained within the picornavirus family are many organisms of importance as vertebrate and human pathogens, shown in the table below.Enteroviruses infect the enteric tract, which is reflected in their name. On the other hand, rhinoviruses infect primarily the nose and the throat. Enteroviruses replicate at 37°C, whereas rhinoviruses grow better at 33°C, as this is the lower temperature of the nose. Enteroviruses are stable under acid conditions and thus they are able to survive exposure to gastric acid. In contrast, rhinoviruses are acid-labile (inactivated or destroyed by low pH conditions) and that is the reason why rhinovirus infections are restricted to the nose and throat. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.08%3A_Positive-Strand_RNA_Viruses_in_Animals/9.8A%3A_Positive-Strand_RNA_Viruses_of_Animals.txt |
Attachment is a specific binding between viral capsid proteins and specific receptors on the host cellular surface.
Learning Objectives
• Differentiate virus attachment and genome entry
Key Points
• Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell.
• Attachment to the receptor can induce the viral envelope protein to undergo changes that results in the fusion of viral and cellular membranes, or changes of non-enveloped virus surface proteins that allow the virus to enter.
• Virions enter the host cell through receptor-mediated endocytosis or membrane fusion.
Key Terms
• capsid: The outer protein shell of a virus.
• receptors: In the field of biochemistry, a receptor is a molecule most often found on the surface of a cell, which receives chemical signals originating externally from the cell.
• virions: An entire virus particle, consisting of an outer protein shell called a capsid and an inner core of nucleic acid.
Viral populations do not grow through cell division, because they are acellular. Instead, they use the machinery and metabolism of a host cell to produce multiple copies of themselves, and they assemble in the cell. The life cycle of viruses differs greatly between species, but they all share the same basic life cycle stages.
Attachment is a specific binding between viral capsid proteins and specific receptors on the host cellular surface. This specificity determines the host range of a virus. For example, HIV infects a limited range of human leukocytes. This is because its surface protein, gp120, specifically interacts with the CD4 molecule, a chemokine receptor, which is most commonly found on the surface of CD4+ T-Cells. This mechanism has evolved to favor those viruses that infect only cells in which they are capable of replication. Attachment to the receptor can induce the viral envelope protein to undergo changes that results in the fusion of viral and cellular membranes, or changes of non-enveloped virus surface proteins that allow the virus to enter.
Penetration follows attachment: Virions enter the host cell through receptor-mediated endocytosis or membrane fusion. This is often called “viral entry. ” The infection of plant and fungal cells is different from that of animal cells. Plants have a rigid cell wall made of cellulose, and fungi one of chitin, so most viruses can get inside these cells only after trauma to the cell wall. However, nearly all plant viruses (such as tobacco mosaic virus) can also move directly from cell to cell, in the form of single-stranded nucleoprotein complexes, through pores called “plasmodesmata”. Bacteria, such as plants, have strong cell walls that a virus must breach to infect the cell. However, given that bacterial cell walls are less thick than plant cell walls due to their much smaller size, some viruses have evolved mechanisms that inject their genome into the bacterial cell across the cell wall, while the viral capsid remains outside
9.8C: Viral Replication and Gene Expression
RNA viruses are classified into distinct groups depending on their genome and mode of replication.
Learning Objectives
• Examine viral gene expression during virus replication
Key Points
• Positive sense, negative sense, double stranded viruses, and retroviruses are RNA viruses with different modes of replication.
• Positive-sense ssRNA viruses (Group IV) have their genome directly utilized as if it were mRNA.
• Replication of viruses involves primarily multiplication of the genome.
• The polarity of single-stranded RNA viruses largely determines the replicative mechanism.
Key Terms
• genome: The complete genetic information (either DNA or, in some viruses, RNA) of an organism, typically expressed in the number of basepairs.
• virus: A submicroscopic infectious organism, now understood to be a non-cellular structure consisting of a core of DNA or RNA surrounded by a protein coat. It requires a living cell to replicate, and often causes disease in the host organism.
• replication: Process by which an object, person, place or idea may be copied mimicked or reproduced.
Replication of viruses primarily involves the multiplication of the viral genome. Replication also involves synthesis of viral messenger RNA (mRNA) from “early” genes (with exceptions for positive sense RNA viruses), viral protein synthesis, possible assembly of viral proteins, then viral genome replication mediated by early or regulatory protein expression. This may be followed, for complex viruses with larger genomes, by one or more further rounds of mRNA synthesis: “late” gene expression is, in general, necessary for structural or virion proteins. Viral replication usually takes place in the cytoplasm.
Viruses that replicate via RNA intermediates need an RNA-dependent RNA- polymerase to replicate their RNA, but animal cells do not seem to possess a suitable enzyme. Therefore, this type of animal RNA virus needs to code for an RNA-dependent RNA polymerase. No viral proteins can be made until viral messenger RNA is available; thus, the nature of the RNA in the virion affects the strategy of the virus: In plus-stranded RNA viruses, the virion (genomic) RNA is the same sense as mRNA and so functions as mRNA. This mRNA can be translated immediately upon infection of the host cell. Examples: poliovirus (picornavirus), togaviruses, and flaviviruses.
RNA viruses are classified into distinct groups depending on their genome and mode of replication (and the numerical groups based on the older Baltimore classification).
Positive-sense ssRNA viruses (Group IV) have their genome directly utilized as if it were mRNA, with host ribosomes translating it into a single protein which is modified by host and viral proteins to form the various proteins needed for replication. One of these includes RNA-dependent RNA polymerase (RNA replicase), which copies the viral RNA to form a double-stranded replicative form, in turn this directs the formation of new virions. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.08%3A_Positive-Strand_RNA_Viruses_in_Animals/9.8B%3A_Virus_Attachment_and_Genome_Entry.txt |
Viruses are released from the host cell following assembly.
Learning Objectives
• Explain how viruses exit host cells
Key Points
• Once replication has been completed and the host cell is exhausted of all resources in making viral progeny, the viruses may begin to leave the cell by several methods.
• Viral exit methods include budding, exocytosis, and cell lysis.
• Budding through the cell envelope, in effect using the cell’s membrane for the virus itself is most effective for viruses that need an envelope.
• This process will slowly use up the cell membrane and eventually lead to the demise of the cell.
Key Terms
• exocytosis: The secretion of substances through cellular membranes, either to excrete waste products or as a regulatory function
• lysogenic: Of, relating to, or causing lysis.
• virions: An entire virus particle, consisting of an outer protein shell called a capsid and an inner core of nucleic acid.
Viral populations do not grow through cell division because they are acellular. Instead, they use the machinery and metabolism of a host cell to produce multiple copies of themselves, and they assemble in the cell. The life cycle of viruses differs between species, but follows the same basic stages.
Viruses can be released from the host cell by lysis, a process that kills the cell by bursting its membrane and cell wall if present. This is a feature of many bacterial and some animal viruses. Some viruses undergo a lysogenic cycle where the viral genome is incorporated by genetic recombination into a specific place in the host’s chromosome. The viral genome is then known as a ” provirus ” or, in the case of bacteriophages a “prophage. ” Whenever the host divides, the viral genome is also replicated. The viral genome is mostly silent within the host. However, at some point, the provirus or prophage may give rise to active virus, which may lyse the host cells. Enveloped viruses (e.g., HIV) typically are released from the host cell by budding. During this process the virus acquires its envelope, which is a modified piece of the host’s plasma or other, internal membrane.
Viral shedding refers to the successful reproduction, expulsion, and host-cell infection caused by virus progeny. Once replication has been completed and the host cell is exhausted of all resources in making viral progeny, the viruses may begin to leave the cell by several methods.
Different types of virus have varying sites of synthesis and replication. For example, synthesis and replication for DNA viruses occur in the cell’s nucleus while it is usually the cytoplasm for RNA viruses. Virus assembly depends on the site of synthesis and such sites are the nucleus, endoplasmic reticulum, and the Golgi apparatus aka Golgi body. Aside from this, assembly also occurs in the viroplasm which is an inclusion body in a cell. When the virus has replicated and multiplied, they would want to leave the infected cell and infect other cells. However, they require an envelope to enclose the DNA as well as to bind with the other healthy cells so that they can infect. The viral envelope is the typical lipid bilayer, derived from the host cell itself and sources usually come from the nuclear membrane, endoplasmic reticulum, Golgi apparatus/body, and plasma membrane. It also depends on where the virus ‘bud’ off from the host.
Budding is a method which viruses use to exit the cell. “Budding” through the cell envelope, in effect using the cell’s membrane for the virus itself is most effective for viruses that need an envelope in the first place. These include enveloped viruses such as HSV, SARS, or smallpox. Prior to budding, the virus may put its own receptor onto the surface of the cell in preparation for the virus to bud through, forming an envelope with the viral receptors already on it. This process will slowly use up the cell membrane and eventually lead to the demise of the cell. This is also how antiviral responses are able to detect virus infected cells.
Other methods for exit would be cell lysis. This method releases the virus from the infected cell by bursting its membrane and this kills the cell as well. Another method is by accumulating the virus particles in vesicles and releasing them via exocytosis. Exocytosis is the process where vesicles containing the virus are secreted/excreted out of the infected cell.
Positive-strand RNA mature virions are infectious. Virions are released following cell lysis. Excess capsids are formed and inclusion bodies may be seen in the cytoplasm.
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Negative-strand RNA viruses are single-stranded viruses that can infect several types of animals.
Learning Objectives
• Explain the mechanism of genome replication in negative-strand RNA viruses
Key Points
• Negative-strand RNA viruses can infect animals, but in several cases they can go from animals into humans, such as the SARS virus of the Ebola Zaire virus.
• The viron RNA is negative sense (complementary to mRNA and cannot encode proteins ), which means it must be replciated over to mRNA before protein production can begin. This is carried out by an RNA-dependent RNA-polymerase.
• Negative-strand viruses can be found in many niches of Earth and are responsible for many common and very deleterious diseases of animals.
Key Terms
• SARS: The SARS coronavirus, sometimes shortened to SARS-CoV, is the virus that causes severe acute respiratory syndrome (SARS).
• RNA-dependent RNA-polymerase: (RdRP, or RNA replicase) An enzyme that catalyzes the replication of RNA from an RNA template. This is in contrast to a typical DNA-dependent RNA polymerase, which catalyzes the transcription of RNA from a DNA template.
The study of animal viruses is important from a veterinary viewpoint, but many animal viruses are also important from a human medical perspective. The emergence of the SARS virus or Ebola Zaire virus in the human population, coming from an animal source, highlights the importance of animals in bearing infectious agents. In addition, research into animal viruses has made an important contribution to our understanding of viruses in general, including their replication, molecular biology, evolution, and interaction with the host. Animal RNA viruses can be classified according to the sense or polarity of their RNA into negative-sense, positive-sense, or ambisense RNA viruses.
The RNA found in a negative-sense virus is not infectious by itself, as it needs to be transcribed into positive-sense RNA. The complementary plus-sense mRNA must be made before proteins can be translated from the viral genome. This RNA negative-strand to positive-strand copying is carried out by an RNA-dependent RNA-polymerase. Each virion that has one negative-strand copy can be transcribed to several positive-sense RNAs. There are several different types of negative-strand RNA viruses that infect animals; two families will be discussed here in further detail.
Rhabdoviruses are a diverse family of single-stranded, negative-sense RNA viruses that can successfully utilize a myriad of ecological niches, ranging from plants and insects, to fish and mammals. This virus family includes pathogens —the rabies virus, vesicular stomatitis virus, potato yellow dwarf virus, etc.—that are of tremendous public health, veterinary, and agricultural significance. Due to the relative simplicity of their genomes and morphology, in recent years rhabdoviruses have become powerful model systems for studying molecular virology.
Paramyxoviruses are a diverse family of non-segmented negative-strand RNA viruses that include many highly pathogenic viruses affecting humans, animals, and birds. In recent years the advent of reverse genetics has led to a greater understanding of their genomics, molecular biology, and viral pathogenesis. Paramyxoviruses cause a range of diseases in animal species: canine distemper virus (dogs), phocine distemper virus (seals), cetacean morbillivirus (dolphins and porpoises), Newcastle disease virus (birds), and rinderpest virus (cattle). Some paramyxoviruses, such as the henipaviruses, are zoonotic pathogens, occurring naturally in an animal host, but also able to infect humans.
9.9B: Attachment and Entry to the Host Cell
For influenza viral propagation to begin, there first must be viron attachment and entry into a host cell.
Learning Objectives
• Explain the role of hemagglutinin in the attachment and entry processes of influenza virus
Key Points
• A glycoprotein on the surface of a virus recognizes a receptor on a host, beginning the attachment process.
• After attachment, the influenza virus is brought into the host cell through an endosome. The low pH of the endosome breaks down the viral capsid and releases the viral contents into the cell.
• A well-described example of this is the influenza virus that relies on hemagglutinin, the glycoprotein that allows the influenza virus to attach to target cells, in this case cells in the human respiratory pathway.
Key Terms
• endosome: An endocytic vacuole through which molecules are internalized during endocytosis pass, en route to lysosomes.
• glycoprotein: A protein with covalently bonded carbohydrates.
• sialic: Of or pertaining to sialic acid or its derivatives.
One of the best understood examples of virus entry into the host cell is the influenza viral infection. The glycoprotein responsible for attachment on the surface of an influenza viral particle is hemagglutinin (HA). HA is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected. HA proteins bind to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes.
HA has two functions. First, it allows the recognition of target vertebrate cells, accomplished through the binding of these cells’ sialic acid-containing receptors. Second, once bound, it facilitates the entry of the viral genome into the target cells by causing the fusion of the host endosomal membrane with the viral membrane. HA binds to the monosaccharide sialic acid that is present on the surface of its target cells, which causes the viral particles to stick to the cell’s surface. The cell membrane then engulfs the virus and the portion of the membrane that encloses it pinches off to form a new membrane-bound compartment within the cell called an endosome, which contains the engulfed virus. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome.
However, as soon as the pH within the endosome drops to about 6.0, the original folded structure of the HA molecule becomes unstable, causing it to partially unfold and release a very hydrophobic portion of its peptide chain that was previously hidden within the protein. This so-called “fusion peptide” acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on. Then, when the rest of the HA molecule refolds into a new structure (which is more stable at the lower pH), it “retracts the grappling hook” and pulls the endosomal membrane right up next to the virus particle’s own membrane, causing the two to fuse together. Once this has happened, the contents of the virus, including its RNA genome, are free to pour out into the cell’s cytoplasm. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.09%3A_Negative-Strand_RNA_Viruses_in_Animals/9.9A%3A_Negative-Strand_RNA_Viruses_of_Animals.txt |
Learning Objectives
• Contrast the roles of hemagglutinin and neuraminidase throughout the major stages of the replicative cycle of influenza A virus
Influenza A follows the typical life cycle of most influenza viruses. The infection and replication is a multi-step process:
• Binding to and entering the cell
• Delivering the genome to a site where it can produce new copies of viral proteins and RNA
• Assembling these components into new viral particles
• Exiting the host cell
Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells, typically in the nose, throat, and lungs of mammals, and the intestines of birds (Step 1 in infection figure ). After the hemagglutinin is cleaved by a protease, the cell imports the virus by endocytosis.
The intracellular details are still being worked out. It is known that virions converge to the microtubule organizing center, interact with acidic endosomes, and finally enter the target endosomes for genome release. Once inside the cell, the acidic conditions in the endosome cause two events to happen:
1. The hemagglutinin protein fuses the viral envelope with the vacuole’s membrane.
2. The M2 ion channel allows protons to move through the viral envelope and acidify the core of the virus, which causes the core to dissemble and release the viral RNA and core proteins.
The viral RNA (vRNA) molecules, accessory proteins, and RNA-dependent RNA polymerase are then released into the cytoplasm (Step 2 in figure). These core proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-dependent RNA polymerase begins transcribing complementary positive-sense vRNA (Steps 3a and b in figure).
The vRNA either enters into the cytoplasm and translated (Step 4) or remains in the nucleus. Newly synthesized viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, Step 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (Step 5a).
Other viral proteins have multiple actions in the host cell—including degrading cellular mRNA and using the released nucleotides for vRNA synthesis, and also inhibiting translation of host-cell mRNAs.
Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA polymerase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion (Step 6). The mature virus buds off from the cell in a sphere of the host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (Step 7). As before, the viruses adhere to the cell through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell. Drugs that inhibit neuraminidase, such as oseltamivir, therefore prevent the release of new infectious viruses and halt viral replication. After the release of new influenza viruses, the host cell dies.
Key Points
• A component of the viral coat, hemagglutinin, binds to the surface of target cells. After binding, the virus fuses and is imported by endocytosis.
• Once the vRNA is released into the cytoplasm, it is transported into the nucleus where it is transcribed. The resulting vRNAs are then transported into the cytoplasm and new viral particles are made.
• The endosome ‘s acidic environment breaks down the viron coat, releasing the vRNA. The acidic environment also promotes the release of the vRNA to proteins that are bound to it.
• Once new viral particles are made in the host cell and bud off, the host cell dies.
Key Terms
• neuraminidase: An antigenic enzyme, found on the surfaces of viruses, that catalyzes the hydrolysis of terminal acylneuraminic residues from oligosaccharides, glycoproteins, and glycolipids.
• hemagglutinin: An antigenic glycoprotein that causes agglutination of red blood cells.
• sialic: Of or pertaining to sialic acid or its derivatives.
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Retroviruses are viruses that are able to reverse transcribe their RNA genome into DNA, which is then integrated into a host genome.
Learning Objectives
• Identify the unique features of retroviruses
Key Points
• In a double stranded RNA form, retroviruses infect a host cell with their genome, and then are reverse transcribed into double stranded DNA, with the DNA then integrated into the home cell genome.
• When integrated into a host genome, a retrovirus is hard to detect and can lay dormant for prolonged periods, having no discernible effect on the host.
• Retroviruses can be human pathogens, and cause many diseases, but have also proven to be invaluable tools when used by molecular biologists.
Key Terms
• reverse transcriptase: An enzyme that catalyzes the formation of DNA from RNA; found in retroviruses.
• transposon: A segment of DNA that can move to a different position within a genome.
• integrase: Any enzyme that integrates viral DNA into that of an infected cell.
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host’s genome by an integrase enzyme. The virus thereafter replicates as part of the host cell’s DNA. Retroviruses are enveloped viruses that belong to the viral family Retroviridae. A special variant of retroviruses are endogenous retroviruses, which are integrated into the genome of the host and inherited across generations. Endogenous retroviruses are a type of transposon.
The virus itself stores its nucleic acid in the form of an mRNA genome and serves as a means of delivering that genome into cells it targets as an obligate parasite (a parasite that cannot live without its host). That process of delivering the genome into cells constitutes the infection. Once in the host’s cell, the RNA strands undergo reverse transcription in the cytoplasm and are integrated into the host’s genome, at which point the retroviral DNA is referred to as a provirus. It is difficult to detect the virus until it has infected the host, where the provirus can stay for months, even years, before becoming active and making new infectious viral particles.
In most viruses, DNA is transcribed into RNA, and then RNA is translated into protein. Retroviruses, however, function differently. Their RNA is reverse-transcribed into DNA, which is integrated into the host cell’s genome (when it becomes a provirus), and then undergoes the usual transcription and translation processes to express the genes carried by the virus. So, the information contained in a retroviral gene is used to generate the corresponding protein via the sequence: RNA → DNA → RNA → protein. Retroviruses can be pathogens of many different hosts, including humans. A notable retrovirus is Human immunodeficiency virus (HIV), the virus responsible for acquired immunodeficiency syndrome (AIDS). As well as infecting a host, some retroviruses can cause cancer.
Finally, retroviruses are proving to be valuable research tools in molecular biology and have been successfully used in gene delivery systems.
9.10B: HIV Attachment and Host Cell Entry
The attachment and fusion of HIV virons to host cells are crucial to HIV infection.
Learning Objectives
• Define the unique aspects of HIV attachment and host cell entry
Key Points
• HIV proteins bind to specific receptors of host cells, most importantly HIV coat proteins gp41 and gp160.
• After attaching to the host, many of the receptors on both the cell and invading virus bind together for fusion of the virus with its host.
• Because HIV attachment is critical for the HIV replication cycle, understanding the specific mechanisms by which HIV attachment occurs has implications for potential treatments of HIV.
Key Terms
• glycoprotein: A protein with covalently bonded carbohydrates.
• macrophages: A type of white blood cell that targets foreign material, including bacteria and viruses.
• capsid: The outer protein shell of a virus.
• chemokine: Any of various cytokines, produced during inflammation, that organize the leukocytes.
• T cells: A lymphocyte, from the thymus, that can recognise specific antigens and can activate or deactivate other immune cells.
HIV entry is the earliest stage of infection in the HIV viral life cycle, occurring when the HIV virus comes into contact with the host cell and introduces viral material into the cell. HIV enters macrophages and CD4-positive T cells (CD4 is a glycoprotein receptor found on cells) by the adsorption of glycoproteins on its surface to receptors on the target cell, followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.
Entry to the cell begins through interaction of the trimeric envelope complex and both CD4 and a chemokine receptor on the host cell on the cell surface. The HIV coat protein, gp120, binds to integrin α4β7, activating LFA-1 (the central integrin involved in the establishment of bridges known as “virological synapses”) which facilitate efficient cell-to-cell spreading of HIV-1.
After attachment, the HIV viron must next fuse with the host cell. The first step in fusion begins after the attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, known as HR1 and HR2, then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.
After HIV has bound to the target cell, the HIV RNA and various enzymes (including reverse transcriptase, integrase, ribonuclease, and protease) are injected into the cell. Because HIV attachment is critical for the HIV replication cycle, understanding the specific mechanisms through which HIV attachment occurs has implications for potential treatments of HIV. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.10%3A_Retroviruses-_Double-Stranded_RNA_Viruses/9.10A%3A_Double-Stranded_RNA_Viruses_-_Retroviruses.txt |
Learning Objectives
• Discover the features of retroviral genomes
The retroviral while in the viral capsid consists of a dimer RNA. It has a cap at the 5′ end and a poly(A) tail at the 3′ end. The RNA genome also has terminal noncoding regions, which are important in replication, and internal regions that encode virion proteins for gene expression.
The 5′ end includes four regions, which are R, U5, PBS, and L.
• The R region is a short repeated sequence at each end of the genome during the reverse transcription in order to ensure correct end-to-end transfer in growing chain.
• U5, on the other hand, is a short unique sequence between R and PBS.
• PBS (primer binding site) consists of 18 bases complementary to 3′ end of the tRNA primer, which supplies an ‘OH group to initiate reverse transcription.
• The L region is an untranslated leader region that give the signal for packaging of genome RNA.
The 3′ end includes 3 regions, which are PPT (polypurine tract), U3, and R.
• PPT (or PP), polypurine tract is the primer for plus-strand DNA synthesis during reverse transcription.
• U3 is a sequence between PPT and R, which has signal that provirus can use in transcription.
• R is the terminal repeated sequence at 3′ end, the same as the R (i.e., repeat region of the 5′ end).
Inbetween the 5′ and 3′ region is the protein encoding region of the retrovirus, consisting of gag proteins, protease (PR), pol proteins and env proteins. Gag proteins are major components of the viral capsid, which are about 2,000-4,000 copies per virion. Protease is expressed differently in different viruses. It functions in proteolytic cleavages during virion maturation to make mature gag and pol proteins. Pol proteins, such as the reverse transcriptase (RT), are responsible for synthesis of viral DNA and integration into host DNA after infection. Finally, env proteins play a role in association and entry of virion into the host cell. Possessing a functional copy of an env gene is what makes retroviruses distinct from retroelements. The env gene serves three distinct functions: enabling the retrovirus to enter/exit host cells through endosomal membrane trafficking, protection from the extracellular environment via the lipid bilayer, and the ability to enter cells. The ability of the retrovirus to bind to its target host cell using specific cell-surface receptors is given by the surface component (SU) of the env, while the ability of the retrovirus to enter the cell via membrane fusion is imparted by the membrane-anchored trans-membrane component (TM). Thus, the env protein is what enables the retrovirus to be infectious.
Please refer to the figure, in it you see all the elements of a retroviral genome and how they interact to contribute to retroviral reverse transcription and integration.
Key Points
• The ends of a retrovirus, both the 5′ and 3′, contain many elements needed for the retroviral life cycle, including the regions referred to as R, U5, PBS, PPT, and U3.
• In between the 5′ and 3′ ends is the protein coding region which includes the gag, pol, and env encoding regions.
• Key to the unique attributes of a retrovirus is the pol region, which encodes a reverse trancriptase (RT), RT is the enzyme which takes the RNA form of the retrovirus genome and converts into DNA, the DNA form of which can integrate into the host genome.
Key Terms
• protease: An enzyme that cuts or cleaves proteins.
• capsid: The outer protein shell of a virus. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.10%3A_Retroviruses-_Double-Stranded_RNA_Viruses/9.10C%3A_Retroviral_RNA_Genome.txt |
Learning Objectives
• Compare and contrast HIV replication to other viruses
Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS). AIDS is a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. HIV can infect dendritic cells (DCs). DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T-cells when the virus is captured in the mucosa by DCs. HIV enters macrophages and T cells by the adsorption of glycoproteins on its surface to receptors on the target cell. This is followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.
Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule. The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or allow the virus to evade the body’s immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a sense DNA from the antisense cDNA. Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus.
This integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To actively produce the virus, certain cellular transcription factors need to be present. The most important of these is NF-κB (NF kappa B), which is upregulated when T-cells become activated. This means that those cells most likely to be killed by HIV are those currently fighting infection. During viral replication, the integrated DNA provirus is transcribed into mRNA, which is then spliced into smaller pieces. These small pieces are exported from the nucleus into the cytoplasm, where they are translated into the regulatory proteins Tat (which encourages new virus production) and Rev.
As the newly produced Rev protein accumulates in the nucleus, it binds to viral mRNAs and allows unspliced RNAs to leave the nucleus, where they are otherwise retained until spliced. At this stage, the structural proteins Gag and Env are produced from the full-length mRNA. The full-length RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles. The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma membrane of the host cell. The Env polyprotein goes through the endoplasmic reticulum and is transported to the Golgi complex. There, it is cleaved by HIV protease and processed into the two HIV envelope glycoproteins, gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell.
Maturation occurs either in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins. This cleavage step can be inhibited by protease inhibitors. The various structural components then assemble to produce a mature HIV virion. The mature virion is then able to infect another cell.
Key Points
• First the HIV viron binds to host cell, after binding the virus and cell fuse, which releases the various enzymes HIV needs to reverse transcribe and integrate into the host genome.
• The reverse transcription of HIV viral RNA to DNA is error prone, causing HIV to have a high mutation rate. This makes it difficult to design treatments against HIV.
• The HIV provirus can stay dormant in the host genome for years. It may become active when the host T cell is itself activated by fighting an infection that the body is facing.
• Understanding the HIV life cycle will help in providing effective treatments against HIV.
Key Terms
• provirus: A virus genome, such as HIV, that integrates itself into the DNA of a host cell so as to be passively replicated along with the host genome.
• reverse transcriptase: An enzyme that catalyzes the formation of DNA from RNA; found in retroviruses.
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DNA viruses are relatively rare in plants, but are responsible for a significant amount of crop damage worldwide.
Learning Objectives
• Differentiate between ssDNA and dsDNA plant viruses
Key Points
• DNA viruses are relatively rare in plants, compared to their RNA counterparts.
• Like most viruses, the genomes of most single stranded DNA viruses are small, encoding only a few proteins, and are therefore dependent on host cell factors for replication.
• Double stranded DNA viruses only infect lower species of plants, such as algae. These viruses are huge dsDNA viruses with genomes ranging from 160 to 560 kb with up to 600 protein-encoding genes, making them distinctly different from viruses infecting higher plants.
• Plant viruses are generally spread through vectors, such as insects, but can also be passed from generation to generation.
Key Terms
• Baltimore Classification System: The Baltimore classification, developed by David Baltimore, is a virus classification system that groups viruses into families, depending on their type of genome (DNA, RNA, single-stranded (ss), double-stranded (ds), etc.) and their method of replication.
• plasmodesmata: Plasmodesmata (singular: plasmodesma) are microscopic channels which traverse the cell walls of plant cells and some algal cells, enabling transport and communication between them.
• capsid: The outer protein shell of a virus.
A DNA virus is a virus with DNA as its genetic material and replicates using a DNA-dependent DNA polymerase. DNA viruses belong to either Group I (double-stranded DNA; dsDNA) or Group II (single-stranded DNA; ssDNA) of the Baltimore classification system for viruses. Single-stranded DNA is usually expanded to double-stranded in infected cells.
DNA viruses are relatively rare in plants. Seventeen percent of plant viruses are ssDNA, while dsDNA viruses infect only lower plants, such as eukaryotic algae. The rarity of dsDNA plant viruses is notable when compared to other taxonomic kingdoms; a quarter of animal viruses and three quarters of bacterial viruses are dsDNA.
Plant viruses are transmitted through a variety of different methods, and generally require breach of protective barriers. Viruses can be spread by direct transfer of sap by contact of a wounded plant with a healthy one, most commonly resulting from agricultural practices, as by damage caused by tools or hands. More often, viruses are spread through vector intermediaries such as insects, nematodes, or protozoa which pick up viruses by feeding on infected plants, and then spread the virus to healthy plants.
Viral transmission from generation to generation occurs in about 20% of plant viruses. When viruses are transmitted by seeds, the seed is infected in the generative cells and the virus is maintained in the germ cells, or occasionally in the seed coat. Little is known about the mechanisms involved in the transmission of plant viruses via seeds, though environment is known to play a key role.
Single-Stranded DNA Viruses
The Geminiviridae and Nanoviridae are the two families of ssDNA viruses known to infect plants. Geminiviridae is the largest known family of single-stranded DNA viruses. It contains a wide range of plant viruses including bean golden mosaic virus, beet curly top virus, maize streak virus, and tomato pseudo-curly top virus, which together are responsible for a significant amount of crop damage worldwide. The genome can either be a single component between 2500-3100 nucleotides, or, in the case of some begomoviruses, two similar-sized components each between 2600 and 2800 nucleotides. They have elongated, geminate capsids with two incomplete T=1 icosahedra joined at the missing vertex. The capsids range in size from 18-20 nm in diameter with a length of about 30 nm. Begomoviruses possess two component genomes separated into two different particles, both of which must usually be transmitted together to initiate a new infection within a suitable host cell. Like many viruses, geminivirus genomes encode only a few proteins, and are therefore dependent on host cell factors for replication. Geminiviruses replication occurs within the nucleus of an infected plant cell via a rolling circle mechanism, similar to that seen in bacteriophages, such as M13, and many plasmids. The resulting ssDNA is packaged into germinate particles in the nucleus. It is not clear if these particles can then leave the nucleus and be transmitted to surrounding cells as virions, or whether ssDNA is trafficked from cell to cell via the plasmodesmata. These viruses tend to be introduced into and initially infect differentiated plant cells, via the piercing mouthparts of the vector insect: however, these cells generally lack the host enzymes necessary for DNA replication, making it difficult for the virus to replicate. To overcome this block geminiviruses can induce plant cells to reenter the cell cycle from a quiescent state so that viral replication can occur.
The Nanoviridae are a family of single-stranded DNA viruses that infect plants. Their name is derived from the Greek word ‘nano’ (dwarf) because of their small genome and their stunting effect on infected plants.
Virions of this family have a capsid and are non-enveloped. The capsid is icosahedral with diameter of 18-20 nm. The genome is composed of 6 to 11 segments of single-stranded circular DNA each ~1 kb in length, with the exact number of segments varying depending on the genus. The segments each encode a single protein. There is a putative stem loop structure in the non-coding region of each segment which has a conserved 9-nucleotide sequence at its apex. Each member has up to 4 segments encoding replication proteins of ~33 kDa. The other segments encode products of 10-20 kDa in size and include a coat protein of ~19 kDa and a protein with a retinoblastoma binding motif.
Double-Stranded DNA Viruses
Double-stranded DNA viruses of plants are rare, and only infect lower plants, such as algae. These viruses (family Phycodnaviridae) are huge dsDNA viruses with genomes ranging from 160 to 560 kb with up to 600 protein-encoding genes, making them distinctly different from viruses infecting higher plants. They are found in aqueous environments throughout the world and play dynamic, albeit largely undocumented, roles in regulating algal communities such as the termination of massive algal blooms commonly referred to as red and brown tides. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.11%3A_DNA_Viruses_in_Eukaryotes/9.11A%3A_Plant_DNA_Viruses.txt |
Most double-stranded DNA viruses replicate within the host cell nucleus.
Learning Objectives
• Differentiate the ways which different classes of dsDNA viruses replicate
Key Points
• From the perspective of the virus, the purpose of viral replication is to allow production and survival of its kind.
• Most double-stranded DNA viruses replicate within the host cell nucleus, including polyomaviruses, adenoviruses, and herpesviruses—poxviruses, however, replicate in the cytoplasm.
• Adenoviruses and herpes viruses encode their own replication factors.
Key Terms
• Okazaki fragments: Okazaki fragments are short, newly synthesized DNA fragments that are formed on the lagging template strand during DNA replication.
• polymerase: Any of various enzymes that catalyze the formation of polymers of DNA or RNA using an existing strand of DNA or RNA as a template.
Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. From the perspective of the virus, the purpose of viral replication is to allow production and survival of its kind. By generating abundant copies of its genome and packaging these copies into viruses, the virus is able to continue infecting new hosts. Replication between viruses is greatly varied and depends on the type of genes involved in them. Most DNA viruses assemble in the nucleus while most RNA viruses develop solely in cytoplasm.
Double-stranded DNA viruses usually must enter the host nucleus before they are able to replicate. Some of these viruses require host cell polymerases to replicate their genome, while others, such as adenoviruses or herpes viruses, encode their own replication factors. However, in either cases, replication of the viral genome is highly dependent on a cellular state permissive to DNA replication and, thus, on the cell cycle. The virus may induce the cell to forcefully undergo cell division, which may lead to transformation of the cell and, ultimately, cancer. An example of a family within this classification is the Adenoviridae.
Polyomaviruses, adenoviruses, and herpesviruses are all nuclear-replicating DNA viruses, each with their own specific approaches to replication. There is only one well-studied example in which a double-stranded DNA virus does not replicate within the nucleus. This is the Poxvirus family, which comprises highly pathogenic viruses that infect vertebrates.
Polyomaviruses
Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds. Most of these viruses, such as BK virus and JC virus, are very common and typically asymptomatic in most human populations studied. However, some polyomaviruses are associated with human disease, particularly in immunocompromised individuals. Some members of the family are oncoviruses, meaning they can cause tumors; they often persist as latent infections in a host without causing disease, but may produce tumors in a host of a different species, or in individuals with ineffective immune systems. The name polyoma refers to the viruses’ ability to produce multiple (poly-) tumors (-oma).
Replication
Prior to genome replication, the processes of viral attachment, entry and uncoating occur. Polyomavirus virions are subsequently endocytosed and transported first to the endoplasmic reticulum where a conformational change occurs; then by an unknown mechanism the virus is exported to the nucleus. Polyomaviruses replicate in the nucleus of the host.
Adenoviruses
Adenoviruses (members of the family Adenoviridae) are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double stranded DNA genome.
Adenoviruses represent the largest nonenveloped viruses. They are able to be transported through the endosome (i.e., envelope fusion is not necessary). The virion also has a unique “spike” or fiber associated with each penton base of the capsid that aids in attachment to the host cell via the receptor on the surface of the host cell.
Replication
Adenoviruses possess a linear dsDNA genome and are able to replicate in the nucleus of vertebrate cells using the host’s replication machinery.
Once the virus has successfully gained entry into the host cell, the endosome acidifies, which alters virus topology by causing capsid components to disband, which in turn destroys the endosome and allows the virion entry into the cytoplasm. It is transported to the nuclear pore, disassembles, and is released into the nucleus. At this point viral gene expression can occur and new virus particles can be generated.
Herpesviruses
Herpesviridae is a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein (“to creep”), referring to the latent, recurring infections typical of this group of viruses. Herpesviridae can cause latent or lytic infections.
At least five species of Herpesviridae – HSV-1 and HSV-2 (both of which can cause orolabial herpes and genital herpes), Varicella zoster virus (which causes chicken-pox and shingles), Epstein-Barr virus (which causes mononucleosis), and Cytomegalovirus – are extremely widespread among humans. More than 90% of adults have been infected with at least one of these, and a latent form of the virus remains in most people. In total, there are 8 herpesvirus types that infect humans: herpes simplex viruses 1 and 2, varicella-zoster virus, EBV (Epstein-Barr virus), human cytomegalovirus, human herpesvirus 6, human herpesvirus 7, and Kaposi’s sarcoma-associated herpesvirus. There are more than 130 herpesviruses, and some are from mammals, birds, fish, reptiles, amphibians, and molluscs.
Replication
All herpesviruses are nuclear-replicating—the viral DNA is transcribed to mRNA within the infected cell’s nucleus. Infection is initiated when a viral particle contacts a cell with specific types of receptor molecules on the cell surface. Following binding of viral envelope glycoproteins to cell membrane receptors, the virion is internalized and dismantled, allowing viral DNA to migrate to the cell nucleus. Within the nucleus, replication of viral DNA and transcription of viral genes occurs.
Poxviruses
Poxviridae is a family of viruses. Human, vertebrates, and arthropods serve as natural hosts. There are currently 69 species in this family, divided among 28 genera, which are divided into two subfamilies. Diseases associated with this family include smallpox.
Poxviridae viral particles (virions) are generally enveloped (external enveloped virion- EEV), though the intracellular mature virion (IMV) form of the virus, which contains different envelope, is also infectious. The virion is exceptionally large—around 200 nm in diameter and 300 nm in length.
Replication
The replication of poxvirus is unusual for a virus with double-stranded DNA genome (dsDNA) because it occurs in the cytoplasm, although this is typical of other large DNA viruses. Poxvirus encodes its own machinery for genome transcription, a DNA dependent RNA polymerase, which makes replication in the cytoplasm possible. Most dsDNA viruses require the host cell’s DNA-dependent RNA polymerase to perform transcription. These host DNA are found in the nucleus, and therefore most dsDNA viruses carry out a part of their infection cycle within the host cell’s nucleus. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.11%3A_DNA_Viruses_in_Eukaryotes/9.11B%3A_Replication_of_Double-Stranded_DNA_Viruses_of_Animals.txt |
Herpes viruses cause a wide range of latent, recurring infections including oral and genital herpes, cytomegalovirus, and chicken pox.
Learning Objectives
• Recognize the attributes of herpes viruses
Key Points
• Herpesviridae is a large family of DNA viruses that cause diseases in animals, including humans.
• The structure of herpes viruses consists of a relatively large double-stranded, linear DNA genome encased within an icosahedral protein cage called the capsid, which is wrapped in a lipid bilayer called the envelope.
• Notable herpes viruses include herpes simplex viruses 1 and 2, Varicella zoster virus (the causative agent of shingles and chicken pox), cytomegalovirus, and Kaposi’s sarcoma virus.
• There is no method to eradicate herpes virus from the body, but antiviral medications, such as acyclovir, can reduce the frequency, duration, and severity of outbreaks.
Key Terms
• tegument: A natural covering of the body or of a bodily organ.
• capsid: The outer protein shell of a virus.
• virion: A single individual particle of a virus (the viral equivalent of a cell).
Herpesviridae is a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpes viruses. The family name is derived from the Greek word herpein (“to creep”), referring to the latent, recurring infections typical of this group of viruses.
Animal herpes viruses all share some common properties. The structure of these viruses consists of a relatively large double-stranded, linear DNA genome encased within an icosahedral protein cage called the capsid, which is wrapped in a lipid bilayer called the envelope. The envelope is joined to the capsid by means of a tegument. This complete particle is known as the virion. HSV-1 and HSV-2 each contain at least 74 genes within their genomes, although speculation over gene crowding allows as many as 84 unique protein-coding genes by 94 putative pen reading frames. These genes encode a variety of proteins involved in forming the capsid, tegument and envelope of the virus, as well as controlling the replication and infectivity of the virus.
Types of herpes viruses
There are nine distinct herpes viruses which cause disease in humans:
• HHV‑1 Herpes simplex virus-1 (HSV-1)
• HHV-2 Herpes simplex virus-2 (HSV-2)
• HHV-3 Varicella zoster virus (VZV)
• HHV-4 Epstein-Barr virus (EBV)
• HHV-5 Cytomegalovirus (CMV)
• HHV-6A/B Roseolovirus, Herpes lymphotropic virus
• HHV-7 Pityriasis Rosea
• HHV-8 Kaposi’s sarcoma-associated herpesvirus
Of particular interest include HSV-1 and HSV-2, which cause oral and/or genital herpes, HSV-3 which causes chickenpox and shingles, and HHV-5 which causes mononucleosis-like symptoms, and HHV-8 which causes a Kaposi’s sarcoma, a cancer of the lymphatic epithelium.
Infection is caused through close contact with an infected individual. Infection is initiated when a viral particle comes in contact with the target cell specific to the individual herpes virus. Viral glycoproteins bind cell surface receptors molecules on the cell surface, followed by virion internalization and disassembly. Viral DNA then migrates to the cell nucleus where replication of viral DNA and transcription of viral genes occurs.
During symptomatic infection, infected cells transcribe lytic viral genes. In some host cells, a small number of viral genes termed latency-associated transcripts accumulate instead. In this fashion, the virus can persist in the cell (and thus the host) indefinitely. While primary infection is often accompanied by a self-limited period of clinical illness, long-term latency is symptom-free.
Reactivation of latent viruses
This has been implicated in a number of diseases (e.g. Shingles, Pityriasis Rosea). Following activation, transcription of viral genes transitions from latency-associated transcripts to multiple lytic genes; these lead to enhanced replication and virus production. Often, lytic activation leads to cell death. Clinically, lytic activation is often accompanied by emergence of non-specific symptoms such as low grade fever, headache, sore throat, malaise, and rash, as well as clinical signs such as swollen or tender lymph nodes, and immunological findings such as reduced levels of natural killer cells.
There is no method to eradicate the herpes virus from the body, but antiviral medications, such as acyclovir, can reduce the frequency, duration, and severity of outbreaks. Analgesics such as ibuprofen and acetaminophen can reduce pain and fever. Topical anesthetic treatments such as prilocaine, lidocaine, benzocaine or tetracaine can also relieve itching and pain.
9.11E: Attachment and Entry of Herpes Simplex
Herpes simplex virus attaches to a host’s cells with viral envelope glycoproteins, which then allows entry of the viral capsid into the host cell.
Learning Objectives
• Illustrate HSV attachment to host cells
Key Points
• The genome encodes for 11 different glycoproteins, four of which, gB, gC, gD and gH, are involved in viral attachment.
• The sequential stages of HSV entry are analogous to those of other viruses.
• First, complementary viral and cell surface receptors bring the viral and host cell membranes into close proximity. Next, the two membranes begin to merge, forming a hemifusion state. Finally, a stable entry pore is formed through which the viral envelope contents are introduced to the host cell.
Key Terms
• glycoprotein: A protein with covalently bonded carbohydrates.
• hemifusion: Partial fusion, or the first stage in full fusion.
• heparan sulfate: A polysaccharide found, associated with protein, in all animal tissue; it has a regulatory function in several biological activities.
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious. They can be spread when an infected person is producing and shedding the virus.
The sequential stages of HSV entry are analogous to those of other viruses. At first, complementary receptors on the virus and the cell surface bring the viral and cell membranes into close proximity. In an intermediate state, the two membranes begin to merge, forming a hemifusion state. Finally, a stable entry pore is formed through which the viral envelope contents are introduced to the host cell.
The genome encodes for 11 different glycoproteins, four of which, gB, gC, gD and gH, are involved in viral attachment. Initial interactions occur when viral envelope glycoprotein C (gC) binds to a cell surface particle called heparan sulfate. A second glycoprotein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors. These include herpesvirus entry mediator (HVEM), nectin-1 and 3-O sulfated heparan sulfate. The receptor provides a strong, fixed attachment to the host cell. These interactions bring the membrane surfaces into mutual proximity and allow for other glycoproteins embedded in the viral envelope to interact with other cell surface molecules. Once bound to the HVEM, gD changes its conformation and interacts with viral glycoproteins H (gH) and L (gL), which form a complex. The interaction of these membrane proteins results in the hemifusion state. Afterward, gB interaction with the gH/gL complex creates an entry pore for the viral capsid. Glycoprotein B interacts with glycosaminoglycans on the surface of the host cell. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.11%3A_DNA_Viruses_in_Eukaryotes/9.11C%3A_Double-Stranded_DNA_Viruses_-_Herpesviruses.txt |
Interferons play pivotal roles in shaping the immune responses in mammals.
Learning Objectives
• List the treatments we have to combat viruses
Key Points
• Vaccines prime the body’s immune system against specific pathogens, but are not effective for treating an infection.
• Many animal viruses are also important from a human medical perspective. The emergence of the SARS virus in the human population, coming from an animal source, highlights the importance of animals in bearing infectious agents. Avian influenza viruses can directly infect humans.
• Immune therapy using immunomodulatory factors, such as interferons, is effective for treatment of hepatitis B and C.
• Immune therapy using immunomodulatory factors, such as interferons, is effective for treatment of hepatitis B and C.
Key Terms
• foot and mouth disease: A highly variable and transmissible viral disease. The virus enters the body through inhalation and affects cattle worldwide.
• interferon: Any of a group of glycoproteins, produced by the immune system, that prevent viral replication in infected cells.
The study of animal viruses is important from a veterinary viewpoint. Many animal viruses are also important from a human medical perspective. The emergence of the SARS virus in the human population, coming from an animal source, highlights the importance of animals in bearing infectious agents. Avian influenza viruses can directly infect humans. In addition research into animal viruses has made an important contribution to our understanding of viruses in general, their replication, molecular biology, evolution, and interaction with the host.
Rhabdoviruses are a diverse family of single stranded, negative sense RNA viruses that can successfully utilize a myriad of ecological niches, ranging from plants and insects, to fish and mammals. This virus family includes pathogens such as rabies virus, vesicular stomatitis virus, and potato yellow dwarf virus that are of tremendous public health, veterinary, and agricultural significance. Due to the relative simplicity of their genomes and morphology, in recent years rhabdoviruses have become powerful model systems for studying molecular virology.
Foot and mouth disease virus (FMDV) is the prototypic member of the Aphthovirus genus in the Picornaviridae family. This picornavirus is the etiological agent of an acute systemic vesicular disease that affects cattle worldwide, foot-and-mouth disease. FMDV is a highly variable and transmissible virus. It enters the body through inhalation. Soon after infection, the single stranded positive RNA that constitutes the viral genome is efficiently translated using a cap-independent mechanism driven by the internal ribosome entry site element (IRES). This process occurs concomitantly with the inhibition of cellular protein synthesis, caused by the expression of viral proteases. In depth knowledge of the molecular basis of the viral cycle is needed to control viral pathogenesis and disease spreading.
Pestiviruses account for important diseases in animals such as Classical swine fever (CSF) and Bovine viral diarrhea / Mucosal disease (BVD/MD). The molecular biology of pestiviruses shares many similarities and peculiarities with the human hepaciviruses. Genome organization and translation strategy are highly similar for the members of both genera. One hallmark of pestiviruses is their unique strategy to establish persistent infection during pregnancy.
Coronavirus (CoV) genome replication takes place in the cytoplasm in a membrane-protected microenvironment, and starts with the translation of the genome to produce the viral replicase.
The first line of defense against viral infections is usually antiviral vaccines, which prime the body’s immune system against specific pathogens. Vaccines traditionally consist of an attenuated (weakened or killed) version of the virus, although many vaccines now target specific immunogenic targets unique to a particular pathogen. Both viral and cellular proteins are required for replication and transcription. CoVs initiate translation by cap-dependent and cap-independent mechanisms. Cell macromolecular synthesis may be controlled after CoV infection by locating some virus proteins in the host cell nucleus. Infection by different coronaviruses cause in the host alteration in the transcription and translation patterns, in the cell cycle, the cytoskeleton, apoptosis and coagulation pathways, inflammation, and immune and stress responses. The balance between genes up- and down-regulated could explain the pathogenesis caused by these viruses.
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, antiviral drugs are usually specific for a particular virus. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
In addition to targeting viral infections directly, some therapeutics work by enhancing the immune responses necessary for viral clearance. One of the best-known of this class of drugs are interferons, which inhibit viral synthesis in infected cells. Interferons (IFNs) play pivotal roles in shaping the immune responses in mammals and are particularly important for the control of viral infections, cell growth, and immune regulation. These proteins rapidly induce an “anti-viral state” in cells that surround infected cells. In order to survive, viruses have evolved multiple strategies to evade the anti-viral effects of IFNs. Elucidating the molecular and cellular biology of the virus-interferon interaction is key to understanding issues such as viral pathogenesis, latency, and the development of novel antivirals.
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Immunodeficiency occurs when the immune system cannot appropriately respond to infections.
Learning Objectives
• Explain the problems associated with immunodeficiency
Key Points
• If a pathogen is allowed to proliferate to certain levels, the immune system can become overwhelmed; immunodeficiency occurs when the immune system fails to respond sufficiently to a pathogen.
• Immunodeficiency can be caused by many factors, including certain pathogens, malnutrition, chemical exposure, radiation exposure, or even extreme stress.
• HIV is a virus that causes immunodeficiency by infecting helper T cells, causing cytotoxic T cells to destroy them.
Key Terms
• phagocyte: a cell of the immune system, such as a neutrophil, macrophage or dendritic cell, that engulfs and destroys viruses, bacteria, and waste materials
• lysis: the disintegration or destruction of cells
• immunodeficiency: a depletion in the body’s natural immune system, or in some component of it
Immunodeficiency
Failures, insufficiencies, or delays at any level of the immune response can allow pathogens or tumor cells to gain a foothold to replicate or proliferate to high enough levels that the immune system becomes overwhelmed, leading to immunodeficiency; it may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including certain medical treatments), malnutrition, or, possibly, by extreme stress. For instance, radiation exposure can destroy populations of lymphocytes, elevating an individual’s susceptibility to infections and cancer. Dozens of genetic disorders result in immunodeficiencies, including Severe Combined Immunodeficiency (SCID), bare lymphocyte syndrome, and MHC II deficiencies. Rarely, primary immunodeficiencies that are present from birth may occur. Neutropenia is one form in which the immune system produces a below-average number of neutrophils, the body’s most abundant phagocytes. As a result, bacterial infections may go unrestricted in the blood, causing serious complications.
HIV/AIDS
Human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS), is a disease of the human immune system caused by infection with human immunodeficiency virus (HIV). During the initial infection, a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses, it interferes more and more with the immune system. The person has a high probability of becoming infected, including from opportunistic infections and tumors that do not usually affect people who have working immune systems.
After the virus enters the body, there is a period of rapid viral replication, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood. This response is accompanied by a marked drop in the number of circulating CD4+ T cells, cells that are or will become helper T cells. The acute viremia, or spreading of the virus, is almost invariably associated with activation of CD8+ T cells (which kill HIV-infected cells) and, subsequently, with antibody production. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts recover.
Ultimately, HIV causes AIDS by depleting CD4+ T cells (helper T cells). This weakens the immune system, allowing opportunistic infections. T cells are essential to the immune response; without them, the body cannot fight infections or kill cancerous cells. The mechanism of CD4+ T cell depletion differs in the acute and chronic phases. During the acute phase, HIV-induced cell lysis and killing of infected cells by cytotoxic T cells accounts for CD4+ T cell depletion, although apoptosis (programmed cell death) may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of the ability of the immune system to generate new T cells appear to account for the slow decline in CD4+ T cell numbers. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.11%3A_DNA_Viruses_in_Eukaryotes/9.11F%3A_Immunodeficiency.txt |
The poxviruses are a family of large, complex, enveloped DNA viruses that infect a variety of vertebrate and invertebrate hosts.
Learning Objectives
• Examine pox viruses for their relevance to human disease and research
Key Points
• The most famous of the poxviruses was smallpox. Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest, which was declared eradicated in 2011.
• The most abundant and simplest infectious form of the poxvirus particle, the mature virion, consists of the viral DNA genome encased in a proteinaceous core and an outer lipoprotein membrane.
• Poxviruses exhibit a temporally-regulated gene expression program: early, intermediate, and late genes drive DNA replication followed by expression of structural proteins necessary for progeny virion assembly.
Key Terms
• recombinant: This term refers to something formed by combining existing elements in a new combination. Thus, the phrase recombinant DNA refers to an organism created in the lab by adding DNA from another species.
• lipoprotein: Any of a large group of complexes of protein and lipid with many biochemical functions.
The poxviruses are a family of large, complex, enveloped DNA viruses that infect a variety of vertebrate and invertebrate hosts. Poxviruses are of significance both medically and scientifically due to their wide distribution, pathogenicity, and cytoplasmic replicative life cycle. Several prominent members, including variola virus (causative agent of smallpox), molluscum contagiosum virus (cause of a common skin infection of young children and immunosuppressed adults) and monkeypox virus (agent of a smallpox-like disease in parts of Africa), are of considerable concern for public health and biodefense.
The most famous of the poxviruses was smallpox. Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning “spotted,” or varus, meaning “pimple. ” The term “smallpox” was first used in Britain in the 15th century to distinguish variola from the “great pox” (syphilis). The last naturally occurring case of smallpox (Variola minor) was diagnosed on October 26, 1977. After vaccination campaigns throughout the 19th and 20thcenturies, the World Health Organization (WHO) certified the eradication of smallpox in 1979. Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest, which was declared eradicated in 2011.
The prototypic and most studied poxvirus, vaccinia virus (VACV), serves as an effective smallpox vaccine, a platform for recombinant vaccines against other pathogens, and an efficient gene expression vector for basic research. Along its approximate 195-kbp double-stranded DNA genome, VACV encodes approximately 200 proteins, ranging in function from viral RNA and DNA synthesis and virion assembly to modulation of host immune defenses.
The most abundant and simplest infectious form of the poxvirus particle, the mature virion (MV), consists of the viral DNA genome encased in a proteinaceous core and an outer lipoprotein membrane with approximately 60 and 25 associated viral proteins, respectively. Following attachment to cell surfaces and fusion with the plasma or endosomal membrane, poxvirus replication is initiated by entry of the viral core into the cytoplasm, where all subsequent steps of the life cycle take place. Poxvirus cores harbor the viral DNA-dependent RNA polymerase and transcription factors necessary for expression of early genes, which constitute nearly half of the viral genome and encode proteins needed for DNA replication and intermediate gene transcription, as well as a large number of immunomodulators.
Poxviruses exhibit a temporally-regulated gene expression program, i.e., expression of early genes encoding DNA replication and intermediate transcription factors triggers the expression of intermediate genes encoding late gene specific transcription factors. Late gene products primarily consist of structural proteins needed for progeny virion assembly, as well as those enzymes destined for incorporation into progeny virions, and used for early gene expression during the next round of infection. Assembly of the MV involves more than 80 viral gene products. In addition, during transit through the cytoplasm, a subset of progeny MVs acquires two additional membrane bilayers, one of which is lost during exocytosis of the particle, to yield the less abundant enveloped virion (EV). Thus, an EV is essentially an MV with an additional membrane in which at least six unique proteins are associated. EVs are antigenically distinct from MVs and are important for efficient virus dissemination in the infected host and protection against immune defenses. In contrast, MVs are released upon cell lysis and may be important for animal-to-animal transmission. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.11%3A_DNA_Viruses_in_Eukaryotes/9.11G%3A_Double-Stranded_DNA_Viruses_-_Pox_Viruses.txt |
Learning Objectives
• Define the characteristics of adenoviruses
Adenoviruses are medium-sized (90–100 nm), non-enveloped, icosahedral viruses composed of a nucleocapsid and a linear, double-stranded DNA (dsDNA) genome. There are 57 described serotypes in humans, which are responsible for 5–10% of upper respiratory infections in children, and many infections in adults as well.
Diversity
Viruses of the family Adenoviridae infect vertebrates, including humans. Among human-tropic viruses classification can be complex; there are 57 accepted human adenovirus types (HAdV-1 to 57) in seven species (Human adenovirus A to G). Different species/serotypes are associated with different conditions:
• respiratory disease (mainly species HAdV-B and C)
• conjunctivitis (HAdV-B and D)
• gastroenteritis (HAdV-F types 40, 41, HAdV-G type 52)
In addition to human viruses, Adenoviridae can be divided into five genera: Mastadenovirus, Aviadenovirus, Atadenovirus, Siadenovirus, and Ichtadenovirus.
Genome
Structurally, adenoviruses represent the largest non-enveloped viruses. They possess non-segmented dsDNA genomes between 26 and 45 Kbp, significantly larger than other dsDNA viruses. The virion also has unique “spike” or fiber associated with each penton base of the capsid that aids in attachment to the host cell via host cell surface receptors.
Viral Entry and Replication
Entry of adenoviruses into the host cell involves two sets of interactions between the virus and the host cell. First, entry into the host cell is initiated by the knob domain of the fiber protein binding to a host cell receptor, either CD46 for the group B human adenovirus serotypes, or the coxsackievirus adenovirus receptor for all other serotypes. Next, a specialized motif in the penton base protein interacts with αv integrin, stimulating internalization of the adenovirus via clathrin-coated pits, resulting in entry of the virion into the host cell within an endosome.
Following internalization, the endosome acidifies, which alters virus topology, causing capsid components to disassociate. These changes, as well as the toxic nature of the pentons, result in the release of the virion into the cytoplasm. With the help of cellular microtubules, the virus is transported to the nuclear pore complex, where viral gene expression can occur.
The adenovirus life cycle is separated by the DNA replication process into two phases: an early and a late phase. In both, a primary transcript that is alternatively spliced to generate monocistronic mRNAs compatible with the host’s ribosome is generated, allowing for the products to be translated.
The early genes are responsible for expressing mainly non-structural, regulatory proteins. The goal of these proteins is threefold: to alter the expression of host proteins necessary for DNA synthesis; to activate other viral genes (such as the virus-encoded DNA polymerase); and to avoid premature death of the infected cell by the host-immune defenses (blockage of apoptosis, blockage of interferon activity, and blockage of MHC class I translocation and expression).
The late phase of the adenovirus lifecycle is focused on producing sufficient quantities of structural protein to pack all the genetic material produced by DNA replication. Once the viral components have successfully been replicated, the virus is assembled into its protein shells and released from the cell as a result of virally induced cell lysis.
Transmission
Adenoviruses are unusually stable to chemical or physical agents and adverse pH conditions, allowing for prolonged survival outside of the body and water. Adenoviruses are spread primarily via respiratory droplets; however, they can also be spread by fecal routes.
Humans infected with adenoviruses display a wide range of responses, from no symptoms at all to the severe infections typical of Adenovirus serotype 14. In the past, U.S. military recruits were vaccinated against two serotypes of adenoviruses, with a corresponding decrease in illnesses caused by those serotypes. Although the vaccine is no longer manufactured for civilians, military personnel can receive the vaccine as of 2014.
Infections
Viral transmission occurs primarily through expectorate, but can also be transmitted via contact with infected objects. Most adenovirus infections affect the upper respiratory tract. These often show up as conjunctivitis, tonsillitis, ear infection, or croup. Adenoviruses, types 40 and 41 can also cause gastroenteritis. A combination of conjunctivitis and tonsillitis is particularly common with adenovirus infections. Some children (especially small ones) can develop adenovirus bronchiolitis or pneumonia, both of which can be severe.
Utilization in Treatment of Unrelated Diseases
Adenovirus is used as a vehicle to administer targeted therapy in the form of recombinant DNA or protein. Specific modifications on fiber proteins are used to target Adenovirus to certain cell types; a major effort is made to limit hepatotoxicity and prevent multiple organ failure. Adenovirus dodecahedron serves as a potent delivery platform for foreign antigens to human myeloid dendritic cells (MDC), and is efficiently presented by MDC to M1-specific CD8+ T lymphocytes.
Key Points
• Adenoviruses are medium-sized (90–100 nm), non-enveloped, icosahedral viruses composed of a nucleocapsid and a linear double-stranded DNA (dsDNA) genome.
• There are 57 described serotypes in humans, which are responsible for 5–10% of upper respiratory infections in children, and many infections in adults as well.
• Adenoviruses bind cell surface receptors on host cells, resulting in entry of the virion into the host cell within an endosome.
• The adenovirus life cycle is separated by the DNA replication process into two phases: an early and a late phase. Early genes are responsible for expressing mainly non-structural, regulatory proteins, while late genes produce structural protein necessary for viral replication.
Key Terms
• endosome: An endocytic vacuole through which molecules are internalized during endocytosis pass, en route to lysosomes.
• recombinant DNA: DNA that has been engineered by splicing together fragments of DNA from multiple species and introduced into the cells of a host.
• integrin: Any of many heterodimeric transmembrane proteins that function as receptors in communication between cells.
• penton: A pentagonal capsomere of an adenovirus capsid.
• capsid: A capsid is the protein shell of a virus. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.11%3A_DNA_Viruses_in_Eukaryotes/9.11H%3A_Double-Stranded_DNA_Viruses-_Adenoviruses.txt |
Hepadnaviruses, retroviruses, use virally encoded reverse transcriptase to convert RNA into DNA.
Learning Objectives
• Differentiate between retroviruses and hepadnaviruses
Key Points
• Retrovirus RNA serves as a template for reverse transcriptase and is copied into DNA.
• Hepadnaviruses are a family of viruses which can cause liver infections in humans and animals.
Key Terms
• endogenous: produced, originating or growing from within
• episome: A segment of DNA that can exist and replicate either autonomously in the cytoplasm or as part of achromosome, mainly found in bacteria.
A well-studied family of this class of viruses includes the retroviruses. One defining feature is the use of reverse transcriptase to convert the positive-sense RNA into DNA. Instead of using the RNA for templates of proteins, they use DNA to create the templates, which is spliced into the host genome using integrase. Replication can then commence with the help of the host cell’s polymerases. A well-studied example of this includes HIV.
A special variant of retroviruses are endogenous retroviruses, which are integrated into the genome of the host and inherited across generations.
The virus itself stores its nucleic acid in the form of a +mRNA (including the 5’cap and 3’PolyA inside the virion ) genome. This then serves as a means of delivery of that genome into cells it targets as an obligate parasite, and constitutes the infection. Once in the host’s cell, the RNA strands undergo reverse transcription in the cytoplasm and are integrated into the host’s genome, at which point the retroviral DNA is referred to as a provirus. It is difficult to detect the virus until it has infected the host.
In most viruses, DNA is transcribed into RNA, and then RNA is translated into protein. However, retroviruses function differently – their RNA is reverse-transcribed into DNA, which is integrated into the host cell’s genome (when it becomes a provirus), and then undergoes the usual transcription and translational processes to express the genes carried by the virus. So, the information contained in a retroviral gene is used to generate the corresponding protein via the sequence: RNA → DNA → RNA → protein. This extends the fundamental process identified by Francis Crick, in which the sequence is: DNA → RNA → protein. Retroviruses are proving to be valuable research tools in molecular biology and have been used successfully in gene delivery systems.
Hepadnaviruses are a family of viruses which can cause liver infections in humans and animals. There are two recognized genera:
• Genus Orthohepadnavirus ; type species: Hepatitis B virus
• Genus Avihepadnavirus ; type species: Duck hepatitis B virus
Hepadnaviruses have very small genomes of partially double-stranded, partially single stranded circular DNA. The genome consists of two uneven strands of DNA. One has a negative-sense orientation, and the other, shorter, strand has a positive-sense orientation.Hepadnaviruses replicate through an RNA intermediate (which they transcribe back into cDNA using reverse transcriptase). The reverse transcriptase becomes covalently linked to a short 3- or 4-nucleotide primer. Most hepadnaviruses will only replicate in specific hosts, and this makes experiments using in vitro methods very difficult.
HBV infection is initiated through viral attachment to an unknown cell surface receptor. The virally encoded DNA polymerase acts upon the DNA, leaving it fully double-stranded. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.11%3A_DNA_Viruses_in_Eukaryotes/9.11I%3A_Retroviruses_and_Hepadnavirus.txt |
Viruses can cause cancer by transforming a normal cell into a malignant cell.
Learning Objectives
• Illustrate how cancer viruses turn normal cells into tumor cells
Key Points
• A direct oncogenic viral mechanism involves either the insertion of additional viral oncogenic genes into the host cell, or the enhancement of already existing oncogenic genes in the genome.
• Tumor viruses come in a variety of forms. Viruses with a DNA genome, such as adenovirus, and viruses with an RNA genome, like the Hepatitis C virus (HCV), can cause cancers. Retroviruses having both DNA and RNA genomes (Human T-lymphotropic virus and hepatitis B virus) can also cause cancers.
• Viruses can become carcinogenic when they integrate into the host cell genome as part of a biological accident, such as polyomaviruses and papillomaviruses.
Key Terms
• oncogenic: Tending to cause the formation of tumors.
• transformation: The alteration of a bacterial cell caused by the transfer of DNA from another, especially if pathogenic.
Worldwide, cancer viruses are estimated to cause 15-20% of all cancers in humans. Most viral infections, however, do not lead to tumor formation; several factors influence the progression from viral infection to cancer development. These factors include host’s genetic makeup, mutation occurrence, exposure to cancer causing agents, and immune impairment.
Viruses typically initiate cancer development by suppressing the host’s immune system, causing inflammation over a long period of time, or by altering host genes. Cancer cells have characteristics that differ from normal cells, such as acquiring the ability to grow uncontrollably. This can result from having control of their own growth signals, losing sensitivity to anti-growth signals, and losing the ability to undergo apoptosis, or programmed cell death.
Cancer cells don’t experience biological aging, and maintain their ability to undergo cell division and growth. Transformation occurs when a virus infects and genetically alters a cell. The infected cell is regulated by the viral genes and has the ability to undergo abnormal new growth. Scientists have been able to discern some commonality among viruses that cause tumors. The tumor viruses or oncoviruses change cells by integrating their genetic material with the host cell’s DNA. Unlike the integration seen in prophages, this is a permanent insertion; the genetic material is never removed.
The insertion mechanism can differ depending on whether the nucleic acid in the virus is DNA or RNA. In DNA viruses, the genetic material can be directly inserted into the host’s DNA. RNA viruses must first transcribe RNA to DNA and then insert the genetic material into the host cell’s DNA.
9.12B: DNA Oncogenic Viruses
An estimated 15 percent of all human cancers worldwide may be attributed to viruses.
Learning Objectives
• Outline DNA oncogenic viruses
Key Points
• Both DNA and RNA viruses have been shown to be capable of causing cancer in humans.
• Epstein-Barr virus, human papilloma virus, hepatitis B virus, and human herpes virus-8 are the four DNA viruses that are capable of causing the development of human cancers.
• The presence of viral gene products in tumor cells that require them to maintain their unchecked proliferation, can provide important targets for directed therapies that specifically can distinguish tumor cells from normal cells.
Key Terms
• oncogenic: Tending to cause the formation of tumors.
There are two classes of cancer viruses: DNA and RNA viruses. Several viruses have been linked to certain types of cancer in humans. These viruses have varying ways of reproduction and represent several different virus families.
DNA Oncogenic Viruses include the following:
• The Epstein-Barr virus has been linked to Burkitt’s lymphoma. This virus infects B cells of the immune system and epithelial cells.
• The hepatitis B virus has been linked to liver cancer in people with chronic infections.
• Human papilloma viruses have been linked to cervical cancer. They also cause warts and benign papillomas.
• Human herpes virus-8 has been linked to the development of Kaposi sarcoma. Kaposi sarcoma causes patches of abnormal tissue to develop in various area of the body including under the skin, in the lining of the mouth, nose, and throat or in other organs.
DNA tumor viruses have two life-styles. In permissive cells, all parts of the viral genome are expressed. This leads to viral replication, cell lysis and cell death. In cells that are non-permissive for replication, viral DNA is usually, but not always, integrated into the cell chromosomes at random sites. Only part of the viral genome is expressed. These are the early control functions of the virus. Viral structural proteins are not made, and no progeny virus is released.
The first DNA tumor viruses to be discovered were rabbit fibroma virus and Shope papilloma virus, both discovered by Richard Shope in the 1930s. Papillomas are benign growths, such as warts, of epithelial cells. They were discovered by making a filtered extract of a tumor from a wild rabbit and injecting the filtrate into another rabbit in which a benign papilloma grew. However, when the filtrate was injected into a domestic rabbit, the result was a carcinoma, a malignant growth. A seminal observation was that it was no longer possible to isolate infectious virus from the malignant growth because the virus had become integrated into the chromosomes of the malignant cells. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.12%3A_Viruses_and_Cancer/9.12A%3A_Cancer_Viruses.txt |
An estimated 15% of all human cancers worldwide may be attributed to viruses.
Learning Objectives
• Classify the viruses with oncogenic properties
Key Points
• Both DNA and RNA viruses have been shown to be capable of causing cancer in humans.
• Human T lymphotrophic virus type 1 and hepatitis C viruses are the two RNA viruses that contribute to human cancers.
• Hepatitis C virus is an enveloped RNA virus capable of causing acute and chronic hepatitis in humans by infecting liver cells. It is estimated 3% of the world’s population are carriers. Chronic infection with hepatitis C virus results in cirrhosis, which in turn can lead to liver cancer.
Key Terms
• oncogenic: Tending to cause the formation of tumors.
• hepatocellular: Of or pertaining to the cells of the liver
There are two classes of cancer viruses: DNA and RNA viruses. Several viruses have been linked to certain types of cancer in humans. These viruses have varying ways of reproduction and represent several different virus families. Specifically, RNA viruses have RNA as their genetic material and can be either single-stranded RNA (ssRNA) or double-stranded (dsRNA). RNA viruses are classified based on the Baltimore classification system and do not take into account viruses with DNA intermediates in their life cycle. Viruses which contain RNA for their genetic material but do include DNA intermediates in their life cycle are called “retroviruses. ” There are numerous RNA oncogenic viruses that have been linked to various cancer types. These various oncogenic viruses include:
1. Human T lymphotrophic virus type 1 (HTLV-I), a retrovirus, has been linked to T-cell leukemia. 2. The hepatitis C virus has been linked to liver cancer in people with chronic infections.
2. Hepatitis viruses includes hepatitis B and hepatitis C have been linked to hepatocellular carcinoma.
3. Human papillomaviruses (HPV) have been linked to cancer of the cervix, anus, penis, vagina/vulva, and some cancers of the head and neck.
4. Kaposi’s sarcoma-associated herpesvirus (HHV-8) has been linked to Kaposi’s sarcoma and primary effusion lymphoma.
5. Epstein-Barr virus (EBV) has been linked to Burkitt’s lymphoma, Hodgkin’s lymphoma, post-transplantation lymphoproliferative disease, and nasopharyngeal carcinoma.
RNA Retroviruses
Retroviruses are different from DNA tumor viruses in that their genome is RNA, but they are similar to many DNA tumor viruses in that the genome is integrated into host genome. Since RNA makes up the genome of the mature virus particle, it must be copied to DNA prior to integration into the host cell chromosome. This lifestyle goes against the central dogma of molecular biology in which that DNA is copied into RNA. The outer envelope comes from the host cell plasma membrane. Coat proteins (surface antigens) are encoded by env (envelope) gene and are glycosylated. One primary gene product is made, but this is cleaved so that there are more than one surface glycoprotein in the mature virus (cleavage is by host enzyme in the Golgi apparatus). The primary protein (before cleavage) is made on ribosomes attached to the endoplasmic reticulum and is a transmembrane (type 1) protein. Inside the membrane is an icosahedral capsid containing proteins encoded by the gag gene (group-specific AntiGen). Gag-encoded proteins also coat the genomic RNA. Again, there is one primary gene product. This is cleaved by a virally-encoded protease (from the pol gene). There are two molecules of genomic RNA per virus particle with a 5′ cap and a 3′ poly A sequence. Thus, the virus is diploid. The RNA is plus sense (same sense as mRNA). About 10 copies of reverse transcriptase are present within the mature virus, these are encoded by the pol gene. Pol gene codes for several functions (again, as with gag and env, a polyprotein is made that is then cut up).
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Learning Objectives
• Demonstrate the ways a virus can go from benign to pathogenic
Humans or other potential viral hosts are constantly exposed to viruses, yet most viral exposure has no effect. However, many viruses that were once benign later become pathogens through a genetic change, which can occur by different mechanisms. One common evolutionary process whereby viral genes change over time is called genetic drift, where individual bases in the DNA or RNA mutate to other bases. Most of these point mutations are “silent”—they do not change the protein that the gene encodes—but others can confer evolutionary advantages such as resistance to antiviral drugs.
The transformation of viruses from benign to pathogenic occurs via two additional processes more specific to viruses. Viral genomes are constantly mutating, producing new forms of these antigens. If one of these new forms of an antigen is sufficiently different from the old antigen, it will no longer bind to the receptors and viruses with these new antigens can evade immunity to the original strain of the virus. When such a change occurs, people who have had the illness in the past will lose their immunity to the new strain and vaccines against the original virus will also become less effective. Two processes drive the antigens to change: antigenic drift and antigenic shift (antigenic drift being the more common).
Antigenic drift is a mechanism for variation by viruses that involves the accumulation of mutations within the antibody -binding sites so that the resulting viruses cannot be inhibited as well by antibodies against previous strains, making it easier for them to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses. The rate of antigenic drift is dependent on two characteristics: the duration of the epidemic and the strength of host immunity. A longer epidemic allows for selection pressure to continue over an extended period of time and stronger host immune responses increase selection pressure for the development of novel antigens.
Alternatively, the change can occur by antigenic shift. Antigenic shift is a specific case of reassortment or viral shift that confers a phenotypic change; it is the process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains. The term is often applied specifically to influenza, as that is the best-known example, but the process also occurs with other viruses, such as the visna virus in sheep. When this happens with influenza viruses, pandemics might result.
Antigenic shift occurs only in influenza A because it infects more than just humans. Affected species include other mammals and birds, giving influenza A the opportunity for a major reorganization of surface antigens. Influenza B and C principally infect humans, minimizing the chance that a reassortment will change its phenotype drastically.
For example, if a pig was infected with a human influenza virus and an avian influenza virus at the same time, an antigenic shift could occur, producing a new virus that had most of the genes from the human virus, but a hemagglutinin or neuraminidase from the avian virus. The resulting new virus would likely be able to infect humans and spread from person to person, but it would have surface proteins (hemagglutinin and/or neuraminidase) not previously seen in influenza viruses that infect humans, and therefore most people would have little or no immune protection. If this new virus causes illness in people and can be transmitted easily from person to person, an influenza pandemic can occur. The most recent 2009 H1N1 outbreak was a result of an antigenic shift and reassortment between human, avian, and swine viruses.
Key Points
• For a virus to become pathogenic, genetic changes must occur. These changes occur via mutations, antigenic shift, or antigenic drift.
• Antigenic drift is the natural mutation over time of known strains, thus small changes may cause a harmless virus to become dangerous.
• Antigenic shift is a specific case of reassortment or viral shift that confers a phenotypic change. It is the process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype that can be more pathogenic than the original strains.
• Antigenic shift is a major driving force behind viruses inhabiting new niches and is responsible for some of the more aggressive human viruses.
Key Terms
• antigenic shift: A specific case of reassortment or viral shift that confers a phenotypic change; it is the process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains.
• antigenic drift: A mechanism for variation by viruses that involves the accumulation of mutations within the antibody-binding sites so that the resulting viruses cannot be inhibited as well by antibodies against previous strains, making it easier for them to spread throughout a partially immune population. | textbooks/bio/Microbiology/Microbiology_(Boundless)/09%3A_Viruses/9.13%3A_Viral_Ecology/9.13A%3A_Emergence_of_Viral_Pathogens.txt |
Learning Objectives
• Show the roles viruses play on ecosystems
Metagenomics is a relatively recent field of study that tries to understand the diversity—especially microbial—of the world around us. Through these studies it is now known that the number of viral particles and number of different viral species in almost every environment on Earth is immense. It is largely believed that viruses by species are the most numerous of any biological entity on earth. This is typified by the role of viruses in marine ecology. A teaspoon of seawater contains about one million viruses.
Viruses are essential to the regulation of saltwater and freshwater ecosystems. Most of these viruses are bacteriophages, which are harmless to plants and animals. They infect and destroy the bacteria in aquatic microbial communities, comprising the most important mechanism of recycling carbon in the marine environment. The organic molecules released from the bacterial cells by the viruses stimulate fresh bacterial and algal growth.
Microorganisms constitute more than 90% of the biomass in the sea. It is estimated that viruses kill approximately 20% of this biomass each day, and that there are 15 times as many viruses in the oceans as there are bacteria and archaea. Viruses are the main agents responsible for the rapid destruction of harmful algal blooms, which often kill other marine life. The number of viruses in the oceans decreases further offshore and deeper into the water, where there are fewer host organisms. The effects of marine viruses are far-reaching; by increasing the amount of photosynthesis in the oceans, viruses are indirectly responsible for reducing the amount of carbon dioxide in the atmosphere by approximately 3 gigatonnes of carbon per year. Like any organism, marine mammals are susceptible to viral infections. In 1988 and 2002, thousands of harbor seals were killed in Europe by the phocine distemper virus. Many other viruses, including caliciviruses, herpesviruses, adenoviruses, and parvoviruses, circulate in marine mammal populations.
As mentioned, marine viruses are mostly bacteriophages, or phages. Phages are obligate intracellular parasites, meaning that they are able to reproduce only while infecting bacteria. Phages therefore are found only within environments that contain bacteria. Most environments contain bacteria, including our own bodies (called normal flora). Often these bacteria are found in large numbers. As a consequence, phages are found almost everywhere. As a rule of thumb, many phage biologists expect that phage population densities will exceed bacterial densities by a ratio of 10:1 or more (VBR or virus-to-bacterium ratio).
Estimates of bacterial numbers on Earth reach approximately 1030; consequently, there is an expectation that 1031 or more individual virus (mostly phage) particles exist, making phages the most numerous category of “organisms” on our planet. Bacteria (along with archaea) appear to be highly diverse and there are possibly millions of species. Phage-ecological interactions therefore are quantitatively vast, with huge numbers of interactions. Phage-ecological interactions are also qualitatively diverse: there are huge numbers of environment types, bacterial-host types, and also individual phage types.
Key Points
• The diversity and numbers of different viruses is incredible.
• In the world’s oceans, 90% of the biomass is microbial, with viruses turning over 20% of that daily. Without the turnover of biomass driven by viruses, many sources of food would not be present for other organisms.
• As bacteria are incredibly diverse, then the viruses that infect them, phages, are even more diverse. As bacteria inhabit almost every niche of the earth, so do viruses.
Key Terms
• ecological: Relating to ecology, the interrelationships of organisms and their environment.
• metagenomics: The study of genomes recovered from environmental samples; especially the differentiation of genomes from multiple organisms or individuals, either in a symbiotic relationship, or at a crime scene.
• intracellular: Inside or within a cell.
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Epidemiology is the study of the patterns, causes, and effects of health and disease conditions in defined populations. It is the cornerstone of public health, and informs policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive medicine. Epidemiologists help with study design, collection and statistical analysis of data, and interpretation and dissemination of results. Epidemiology has helped develop methodology used in clinical research, public health studies and, to a lesser extent, basic research in the biological sciences.
• 10.1: Principles of Epidemiology
Epidemiology is the study of the patterns, causes, and effects of health and disease conditions in defined populations. It is the cornerstone of public health, and informs policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive medicine. Epidemiologists help with study design, collection and statistical analysis of data, and interpretation and dissemination of results.
• 10.2: Pathogen Identification
• 10.3: Disease Patterns
• 10.4: Nosocomial Infections
A nosocomial infection is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is sometimes instead called a health care–associated infection. Such an infection can be acquired in hospital, nursing home, rehabilitation facility, outpatient clinic, or other clinical settings. Infection is spread to the susceptible patient in the clinical setting by various means.
• 10.5: Epidemiology and Public Health
Epidemiology is the study and analysis of the distribution (who, when, and where) and determinants of health and disease conditions in defined populations.
Thumbnail: Mary Mallon, better known as Typhoid Mary, was the first person in the United States identified as an asymptomatic carrier of the pathogen associated with typhoid fever. She was presumed to have infected 22 people, three of whom died, over the course of her career as a cook. (Public Domain).
10: Epidemiology
Epidemiology is the study of the patterns, causes, and effects of health and disease conditions in defined populations. It is the cornerstone of public health, and informs policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive medicine. Epidemiologists help with study design, collection and statistical analysis of data, and interpretation and dissemination of results. Epidemiology has helped develop methodology used in clinical research, public health studies and, to a lesser extent, basic research in the biological sciences.
10.01: Principles of Epidemiology
Learning Objectives
• Describe the key events in the development of the field of epidemiology
Epidemiology is the study of the patterns, causes, and effects of health and disease conditions in defined populations. It is the cornerstone of public health, and informs policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive medicine. Epidemiologists help with study design, collection and statistical analysis of data, and interpretation and dissemination of results. Epidemiology has helped develop methodology used in clinical research, public health studies and, to a lesser extent, basic research in the biological sciences.
The Greek physician Hippocrates is known as the father of medicine, and was the first epidemiologist. Hippocrates sought a logic to sickness. He is the first person known to have examined the relationships between the occurrence of disease and environmental influences. Hippocrates believed sickness of the human body to be caused by an imbalance of the four Humors (air, fire, water and earth “atoms”). The cure to the sickness was to remove or add the humor in question to balance the body. This belief led to the application of bloodletting and dieting in medicine.
The distinction between “epidemic” and “endemic” was first drawn by Hippocrates, to distinguish between diseases that are “visited upon” a population (epidemic) from those that “reside within” a population (endemic). The term “epidemiology” appears to have first been used to describe the study of epidemics in 1802 by the Spanish physician Joaquín de Villalba in Epidemiología Española. Epidemiologists also study the interaction of diseases in a population, a condition known as a syndemic.
One of the earliest theories on the origin of disease was that it was primarily the fault of human luxury. This was expressed by philosophers such as Plato and Rousseau, and social critics like Jonathan Swift. In the middle of the 16th century, a doctor from Verona named Girolamo Fracastoro was the first to propose a theory that these very small, unseeable, particles that cause disease were alive. They were considered to be able to spread by air, multiply by themselves and to be destroyable by fire. In 1543 he wrote a book De contagione et contagiosis morbis, in which he was the first to promote personal and environmental hygiene to prevent disease. The development of a sufficiently powerful microscope by Anton van Leeuwenhoek in 1675 provided visual evidence of living particles consistent with a germ theory of disease.
Dr. John Snow is famous for his investigations into the causes of the 19th century cholera epidemics, and is also known as the father of (modern) epidemiology. He began by noticing the significantly higher death rates in two areas supplied by Southwark Company. His identification of the Broad Street pump as the cause of the Soho epidemic is considered the classic example of epidemiology. He used chlorine in an attempt to clean the water and had the handle removed, thus ending the outbreak. This has been perceived as a major event in the history of public health and regarded as the founding event of the science of epidemiology, having helped shape public health policies around the world. However, Snow’s research and preventive measures to avoid further outbreaks were not fully accepted or put into practice until after his death.
In the early 20th century, mathematical methods were introduced into epidemiology by Ronald Ross, Anderson Gray McKendrick and others. Another breakthrough was the 1954 publication of the results of a British Doctors Study, led by Richard Doll and Austin Bradford Hill, which lent very strong statistical support to the suspicion that tobacco smoking was linked to lung cancer.
Key Points
• The Greek physician Hippocrates is known as the father of medicine, and was the first epidemiologist.
• The distinction between ” epidemic ” and “endemic” was first drawn by Hippocrates, to distinguish between diseases that are “visited upon” a population (epidemic) from those that “reside within” a population (endemic).
• In the early 20th century, mathematical methods were introduced into epidemiology adding statistical support to the field (i.e. the suspicion that tobacco smoking was linked to lung cancer was backed by statistics).
Key Terms
• endemic: (Especially of diseases. ) Prevalent in a particular area or region.
• epidemic: A widespread disease that affects many individuals in a population.
• epidemiology: The branch of a science dealing with the spread and control of diseases, computer viruses, concepts, etc., throughout populations or systems. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.01%3A_Principles_of_Epidemiology/10.1A%3A_History_of_Epidemiology.txt |
Epidemiological studies include disease etiology, disease surveillance and screening, biomonitoring, and clinical trials.
Learning Objectives
• Discuss the various factors that characterize epidemiology
Key Points
• Epidemiologists rely on other scientific disciplines like biology to better understand disease processes, statistics to make efficient use of the data and draw appropriate conclusions, social sciences to better understand proximate and distal causes, and engineering for exposure assessment.
• Epidemiologists employ a range of study designs from the observational to experimental. Its study designs are generally categorized as descriptive, analytical, and experimental.
• The identification of causal relationships between disease exposures and outcomes is an important aspect of epidemiology.
Key Terms
• epidemiologist: A scientist (often a medical doctor) who specializes in epidemiology.
• causal: A cause of something; causing.
Major areas of epidemiological study include disease etiology, outbreak investigation, disease surveillance and screening, biomonitoring, and comparisons of treatment effects such as in clinical trials. Epidemiologists rely on other scientific disciplines like biology to better understand disease processes, statistics to make efficient use of the data and draw appropriate conclusions, social sciences to better understand proximate and distal causes, and engineering for exposure assessment.
Epidemiological studies are aimed, where possible, at revealing unbiased relationships between exposures such as alcohol or smoking, biological agents, stress, or chemicals to mortality or morbidity. Epidemiologists employ a range of study designs from the observational to experimental. Its study designs are generally categorized as descriptive, analytical (aiming to further examine known associations or hypothesized relationships), and experimental (a term often equated with clinical or community trials of treatments and other interventions).
In observational studies, nature is allowed to “take its course”, as epidemiologists observe from the sidelines. Observational studies have two components: descriptive or analytical. Descriptive observations pertain to the “who, what, where and when of health-related state occurrence”. On the other hand, analytical observations deal more with the “how” of a health-related event.
Controversially, in experimental studies, the epidemiologist is the one in control of all of the factors relating to the particular case study. Experimental epidemiology contains three case types: randomized control trials (often used for new medicine or drug testing), field trials (conducted on those at a high risk of conducting a disease), and community trials (research on social originating diseases).
The identification of causal relationships between these exposures and outcomes is an important aspect of epidemiology. It is nearly impossible to say with perfect accuracy how even the most simple physical systems behave beyond the immediate future. The complex field of epidemiology, which draws on biology, sociology, mathematics, statistics, anthropology, psychology, and policy only makes analysis even more challenging.
A common theme in much of the epidemiological literature is that “correlation does not imply causation. ” For epidemiologists, the key is in the term inference. Epidemiologists use gathered data and a broad range of biomedical and psychosocial theories in an iterative way to generate or expand theory, to test hypotheses, and to make educated, informed assertions about which relationships are causal, and about exactly how they are causal.
10.1C: The Vocabulary Epidemiology
Learning Objectives
• Compare and contrast the following concepts: epidemic, endemic, pandemic; incidence vs prevalence; morbidity vs mortality; incubation, latency, acute, decline and convalescent periods
Epidemiology, literally meaning “the study of what is upon the people”, is derived from Greek: epi, meaning “upon, among”, demos, meaning “people, district”, and logos, meaning “study, word, discourse”, suggesting that it applies only to human populations. However, the term is widely used in studies of zoological populations (veterinary epidemiology) and of plant populations (botanical or plant disease epidemiology).
Outbreak is a term used in epidemiology to describe an occurrence of disease greater than would otherwise be expected at a particular time and place. It may affect a small and localized group or impact upon thousands of people across an entire continent. An asymptomatic carrier (healthy carrier or just carrier) is a person or other organism that has contracted an infectious disease, but who displays no symptoms. Although unaffected by the disease themselves, carriers can transmit it to others. A number of animal species act as vectors of human diseases.
EPIDEMIC, ENDEMIC OR PANDEMIC?
The distinction between “epidemic” and “endemic” was first drawn by Hippocrates, to distinguish between diseases that are “visited upon” a population (epidemic) from those that “reside within” a population (endemic). A pandemic is an epidemic of infectious disease that has spread through human populations across a large region; for instance multiple continents, or even worldwide. The term epidemiology is now widely applied to cover the description and causation of not only epidemic disease, but of disease in general, and even many non-disease health-related conditions, such as high blood pressure and obesity.
INCIDENCE VS. PREVALENCE
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during a time period, it is better expressed as the incidence rate which is the number of new cases per population in a given time period. Incidence should not be confused with prevalence, which is a measure of the total number of cases of disease in a population rather than the rate of occurrence of new cases. Thus, incidence conveys information about the risk of contracting the disease, whereas prevalence indicates how widespread the disease is. Prevalence is the proportion of the total number of cases to the total population and is more a measure of the burden of the disease on society.
MORBIDITY VS. MORTALITY
Morbidity is a diseased state, disability, or poor health due to any cause. The term may be used to refer to the existence of any form of disease, or to the degree that a health condition affects the patient. In epidemiology, the term morbidity rate can refer to either the incidence rate, or the prevalence of a disease, or medical condition. This measure of sickness is contrasted with the mortality rate of a condition, which is the proportion of people dying during a given time interval.
PHASES OF DISEASES
Epidemiologists are interested in determining the progression of a disease. In an infectious disease, the incubation period is the time between infection and the appearance of symptoms (acute period). Thelatency period is the time between infection and the ability of the disease to spread to another person, which may precede, follow, or be simultaneous with the appearance of symptoms. In most illnesses, the acute period is followed by the decline period (symptoms get better) and convalescent (or recovery) period.
Some viruses also exhibit a dormant phase, called viral latency, in which the virus hides in the body in an inactive state. For example, varicella zoster virus causes chickenpox in the acute phase; after recovery from chickenpox, the virus may remain dormant in nerve cells for many years, and later cause herpes zoster (shingles).
Key Points
• Outbreak is a term used in epidemiology to describe an occurrence of disease greater than would otherwise be expected at a particular time and place.
• An asymptomatic carrier is a person or other organism that has contracted an infectious disease, but who displays no symptoms.
• Diseases that are “visited upon” a population are epidemic, whereas those that “reside within” a population are endemic. A pandemic is an epidemic of infectious disease that has spread through human populations across a large region.
• Incidence is a measure of the risk of developing some new condition within a specified period of time. Prevalence is a measure of the total number of cases of disease in a population.
• Morbidity is a diseased state, disability, or poor health due to any cause. The mortality rate of a condition is the proportion of people dying from it during a given time interval.
• The progression of an infection usually follows these phases: infection, incubation period, acute period, decline period, and convalescent period.
Key Terms
• epidemiology: The branch of a science dealing with the spread and control of diseases, computer viruses, concepts, etc., throughout populations or systems. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.01%3A_Principles_of_Epidemiology/10.1B%3A_The_Science_of_Epidemiology.txt |
Learning Objectives
• List Koch’s postulates
Koch’s postulates are four criteria designed to establish a causal relationship between a causative microbe and a disease. The postulates were formulated by Robert Koch and Friedrich Loeffler in 1884 and refined and published by Koch in 1890. Koch applied the postulates to establish the etiology of anthrax and tuberculosis, but they have been generalized to other diseases.
Koch’s postulates were developed in the 19th century as general guidelines to identify pathogens that could be isolated with the techniques of the day. Even in Koch’s time, it was recognized that some infectious agents were clearly responsible for disease even though they did not fulfill all of the postulates. Attempts to rigidly apply Koch’s postulates to the diagnosis of viral diseases in the late 19th century, at a time when viruses could not be seen or isolated in culture, may have impeded the early development of the field of virology. Currently, a number of infectious agents are accepted as the cause of disease despite their not fulfilling all of Koch’s postulates. Therefore, while Koch’s postulates retain historical importance and continue to inform the approach to microbiologic diagnosis, fulfillment of all four postulates is not required to demonstrate causality.
Koch’s postulates
Koch’s postulates are the following:
1. The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms.
2. The microorganism must be isolated from a diseased organism and grown in pure culture.
3. The cultured microorganism should cause disease when introduced into a healthy organism.
4. The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.
Koch’s postulates have also influenced scientists who examine microbial pathogenesis from a molecular point of view. In the 1980s, a molecular version of Koch’s postulates was developed to guide the identification of microbial genes encoding virulence factors.
Key Points
• The postulates were formulated by Robert Koch and Friedrich Loeffler in 1884 and refined and published by Koch in 1890.
• Postulate 1: The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms.
• Postulate 2: The microorganism must be isolated from a diseased organism and grown in pure culture.
• Postulate 3: The cultured microorganism should cause disease when introduced into a healthy organism.
• Postulate 4: The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.
Key Terms
• Koch’s postulates: four criteria designed to establish a causal relationship between a causative microbe and a disease
• postulate: A fundamental element; a basic principle.
10.1E: Exceptions to Kochs Postulates
Learning Objectives
• Recognize the exception to Koch’s postulates
Koch’s postulates were developed in the 19th century as general guidelines to identify pathogens that could be isolated with the techniques of the day. Even in Koch’s time, it was recognized that some infectious agents were clearly responsible for disease, even though they did not fulfill all of the postulates. Currently, a number of infectious agents are accepted as the cause of diseases despite their not fulfilling all of Koch’s postulates. Therefore, while Koch’s postulates retain historical importance and continue to inform the approach to microbiologic diagnosis, fulfillment of all four postulates is not required to demonstrate causality.
Koch abandoned the requirement of the first postulate altogether when he discovered asymptomatic carriers of cholera and, later, of typhoid fever. Asymptomatic or subclinical infection carriers are now known to be a common feature of many infectious diseases, especially viruses such as polio, herpes simplex, HIV, and hepatitis C. Specifically, all doctors and virologists agree that the poliovirus causes paralysis in just a few infected subjects, and the success of the polio vaccine in preventing disease supports the conviction that the poliovirus is the causative agent.
The second postulate may also be suspended for certain microorganisms or entities that cannot (at the present time) be grown in pure culture, such as prions responsible for Creutzfeldt–Jakob disease.
The third postulate specifies “should”, not “must”, because as Koch himself proved in regard to both tuberculosis and cholera, that not all organisms exposed to an infectious agent will acquire the infection. Noninfection may be due to such factors as general health and proper immune functioning; acquired immunity from previous exposure or vaccination; or genetic immunity, as with the resistance to malaria conferred by possessing at least one sickle cell allele.
In summary, a body of evidence that satisfies Koch’s postulates is sufficient but not necessary to establish causation.
Key Points
• Koch abandoned the requirement of the first postulate altogether when he discovered asymptomatic carriers of cholera.
• The second postulate may also be suspended for certain microorganisms or entities that cannot (at the present time) be grown in pure culture, such as prions responsible for Creutzfeldt–Jakob disease.
• The third postulate specifies “should”, not “must”, because as Koch himself proved in regard to both tuberculosis and cholera, not all organisms exposed to an infectious agent will acquire the infection.
Key Terms
• asymptomatic: not exhibiting any symptoms of disease.
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Learning Objectives
• Recognize the steps taken by epidemiologists when investigating disease outbreaks
Outbreak is a term used in epidemiology to describe an occurrence of disease greater than would otherwise be expected at a particular time and place. It may affect a small and localized group or impact thousands of people across an entire continent. Two linked cases of a rare infectious disease may be sufficient to constitute an outbreak. Outbreaks may also refer to endemics that affect a particular place or group, epidemics that affect a region in a country or a group of countries, and pandemics that describe global disease outbreaks.
The epidemiology profession has developed a number of widely accepted steps when investigating disease outbreaks. As described by the Centers for Disease Control and Prevention, these include the following:
1. Verify the diagnosis related to the outbreak.
2. Identify the existence of the outbreak (if the group of ill persons is normal for the time of year, geographic area, etc. ).
3. Create a case definition to define who/what is included as a case.
4. Map the spread of the outbreak.
5. Develop a hypothesis (if there appears to be a cause for the outbreak).
6. Study hypothesis (collect data and perform analysis).
7. Refine hypothesis and carry out further study.
8. Develop and implement control and prevention systems.
9. Release findings to greater communities.
There are several outbreak patterns that can be useful in identifying the transmission method or source and predicting the future rate of infection.
1. Common source – All victims acquire the infection from the same source (e.g. a contaminated water supply).
2. Continuous source – Common source outbreak where the exposure occurs over multiple incubation periods.
3. Point source – Common source outbreak where the exposure occurs in less than one incubation period.
4. Propagated – Transmission occurs from person to person.
Each has a distinctive epidemic curve, or histogram of case infections and deaths.
Outbreaks can also be:
1. Behavioral risk related (e.g. sexually transmitted diseases, increased risk due to malnutrition)
2. Zoonotic – The infectious agent is endemic to an animal population.
Key Points
• Outbreaks may also refer to endemics that affect a particular place or group, epidemics that affect a region in a country or a group of countries, or pandemics that describe global disease outbreaks.
• The epidemiology profession has developed a number of widely accepted steps to investigate a disease occurrence.
• Outbreak patterns, which can be useful in identifying the transmission method or source, and predicting the future rate of infection include common source, continuous source, point source, and propagated source.
• Outbreaks can be behavioral risk related (e.g., sexually transmitted diseases, increased risk due to malnutrition) or zoonotic (e.g. the infectious agent is endemic to an animal population ).
Key Terms
• outbreak: A term used in epidemiology to describe an occurrence of disease greater than would otherwise be expected at a particular time and place.
• epidemic: A widespread disease that affects many individuals in a population.
• pandemic: A disease that hits a wide geographical area and affects a large proportion of the population. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.02%3A_Pathogen_Identification/10.2A%3A_Occurrence_of_a_Disease.txt |
The severity and duration of diseases vary greatly and are important for epidemiological studies.
Learning Objectives
• Discuss the severity and various types of disease duration, including: acute, chronic, flare-up, refractory, progressive, remission and a cure
Key Points
• Severity of illness is defined as the extent of organ system derangement or physiologic decompensation of a patient, and in general an illness is classified into minor, moderate, major, and extreme.
• In an infectious disease, the incubation period is the time between infection and the appearance of symptoms, the latency period is the time between infection and the ability to spread to another person, and the viral latency is the time the virus hides in the body in an inactive state.
• Disease duration can encompass one or more of the following: an acute disease, a chronic disease, a flare-up, a refractory disease is a disease, a progressive disease, or a cure.
• The scope of a disease, whether it is localized, disseminated, or systemic also affects its severity and duration.
• The International Classification of Diseases (ICD) is known as a health care classification system that provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or disease.
Key Terms
• severity: the degree of something undesirable; badness or seriousness.
• duration: an amount of time or a particular time interval
Severity of illness is defined as the extent of organ system derangement or physiologic decompensation of a patient. It gives a medical classification into minor, moderate, major, and extreme that is meant to provide a basis for evaluating hospital resource use or to establish patient care guidelines.
In an infectious disease, the incubation period is the time between infection and the appearance of symptoms. The latency period is the time between infection and the ability of the disease to spread to another person, which may precede, follow, or be simultaneous with the appearance of symptoms. Some viruses also exhibit a dormant phase, called viral latency, in which the virus hides in the body in an inactive state.
Disease duration can be one of the following:
1. An acute disease is a short-lived disease, like the common cold.
2. A chronic disease is one that lasts for a long time, usually at least six months. During that time, it may be constantly present, or it may go into remission and periodically relapse. A chronic disease may be stable (does not get any worse) or it may be progressive (gets worse over time). Some chronic diseases can be permanently cured. Most chronic diseases can be beneficially treated, even if they cannot be permanently cured.
3. A flare-up can refer to either the recurrence of symptoms or an onset of more severe symptoms.
4. A refractory disease is a disease that resists treatment, especially an individual case that resists treatment more than is normal for the specific disease in question.
5. A progressive disease is a disease whose typical natural course is the worsening of the disease until death, serious debility, or organ failure occurs. Slowly progressive diseases are also chronic diseases; many are also degenerative diseases. The opposite of progressive disease is stable disease or static disease: a medical condition that exists, but does not get better or worse.
6. A cure is the end of a medical condition or a treatment that is very likely to end it, while remission refers to the disappearance, possibly temporarily, of symptoms. Complete remission is the best possible outcome for incurable diseases.
The scope of a disease also affects its severity and duration:
1. A localized disease is one that affects only one part of the body, such as athlete’s foot or an eye infection.
2. A disseminated disease has spread to other parts; with cancer, this is usually called metastatic disease.
3. A systemic disease is a disease that affects the entire body, such as influenza or high blood pressure.
The International Classification of Diseases (most commonly known by the abbreviation ICD) is according to its publisher, the United Nations-sponsored World Health Organization, and is considered “the standard diagnostic tool for epidemiology, health management and clinical purposes. ” It is known as a health care classification system that provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or disease. Under this system, every health condition can be assigned to a unique category and given a code, up to six characters long. Such categories can include a set of similar diseases.The International Classification of Diseases is published by the World Health Organization (WHO) and is used worldwide for morbidity and mortality statistics, reimbursement systems, and automated decision support in health care. This system is designed to promote international comparability in the collection, processing, classification, and presentation of these statistics. The ICD is a core classification of the WHO Family of International Classifications (WHO-FIC). | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.02%3A_Pathogen_Identification/10.2B%3A__Disease_Severity_and_Duration.txt |
Host-pathogen interactions are the interactions taking place between a pathogen (e.g. virus, bacteria) and their host (e.g. humans, plants).
Learning Objectives
• Differentiate between primary and opportunistic pathogens in regards to host involvement
Key Points
• All pathogens damage their host to some extent, usually resulting in an infectious disease from the interplay between the pathogens and the defenses of the hosts they infect.
• Clinicians classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens.
• Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence is, in part, a necessary consequence of their need to reproduce and spread.
• Organisms which cause an infectious disease in a host with depressed resistance are classified as opportunistic pathogens.
Key Terms
• host: A cell or organism which harbors another organism or biological entity, usually a parasite.
• pathogen: Any organism or substance, especially a microorganism, capable of causing disease, such as bacteria, viruses, protozoa, or fungi. Microorganisms are not considered to be pathogenic until they have reached a population size that is large enough to cause disease.
Host-pathogen interactions are the interactions that take place between a pathogen (e.g. virus, bacteria ) and their host (e.g. humans, plants). By definition, all pathogens damage their host to some extent. Infectious diseases result from the interplay between the pathogens and the defenses of the hosts they infect. The appearance and severity of disease resulting from the presence of any pathogen depends upon the ability of that pathogen to damage the host as well as the ability of the host to resist the pathogen.
Clinicians therefore classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens.
Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common primary pathogens of humans only infect humans; however many serious diseases are caused by organisms acquired from the environment or which infect non-human hosts.
Organisms which cause an infectious disease in a host with depressed resistance are classified as opportunistic pathogens. Opportunistic diseases may be caused by microbes that are ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract, and they may also result from (otherwise innocuous) microbes acquired from other hosts or from the environment as a result of traumatic introduction. An opportunistic disease requires impairment of host defenses, which may occur as a result of several factors such as genetic defects, exposure to antimicrobial drugs or immunosuppressive chemicals, exposure to ionizing radiation, or as a result of an infectious disease with immunosuppressive activity. Primary pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host.
10.2D: Identification of Microbes Based on Molecular Genetics
Modern nucleic acid-based microbial detection methods make it possible to identify microbes that are associated with a disease.
Learning Objectives
• Describe the components of Molecular Koch’s postulates
Key Points
• Nucleic acid -based detection methods are very sensitive.
• Molecular Koch’s postulates are a set of experimental criteria that must be satisfied to show that a gene found in a pathogenic microorganism encodes a product that contributes to the disease caused by the pathogen.
• After virulent factors have been identified, it is possible to develop a vaccine against the factors.
• For many pathogenic microorganisms, it is not currently possible to apply molecular genetic techniques to a gene in question.
Key Terms
• genetic: Relating to genetics or genes.
• nucleic acid: Any acidic, chainlike biological macromolecule consisting of repeating units of phosphoric acid, sugar, and purine and pyrimidine bases; they are involved in the preservation, replication, and expression of hereditary information in every living cell.
• virulent: Highly infectious, malignant, or deadly.
• genetics: the branch of biology that deals with the transmission and variation of inherited characteristics, in particular chromosomes and DNA
Modern nucleic acid-based microbial detection methods make it possible to identify microbes that are associated with a disease. Nucleic acid-based detection methods are very sensitive, and they can often detect the very low levels of viruses that are found in healthy people without disease.
The use of these new methods has led to revised versions of Koch’s postulates. Molecular Koch’s postulates are a set of experimental criteria that must be satisfied to show that a gene found in a pathogenic microorganism encodes a product that contributes to the disease caused by the pathogen. Genes that satisfy molecular Koch’s postulates are often referred to as virulence factors (i.e., what makes the pathogen virulent). The following set of Koch’s postulates for the 21st century have been suggested:
1. A nucleic acid sequence belonging to a putative pathogen should be present in most cases of an infectious disease. Microbial nucleic acids should be found, preferentially in those organs or gross anatomic sites known to be diseased and not in those organs that lack pathology.
2. Fewer, or no, copies of the pathogen-associated nucleic acid sequences should occur in hosts or tissues without disease.
3. With resolution of the disease, the copy number of pathogen-associated nucleic acid sequences should decrease or become undetectable. With clinical relapse, the opposite should occur.
4. When sequence detection predates disease, or the sequence copy number correlates with severity of disease or pathology, the sequence-disease association is more likely to be a causal relationship.
5. The nature of the microorganism inferred from the available sequence should be consistent with the known biological characteristics of that group of organisms.
6. Tissue-sequence correlates should be sought at the cellular level. Efforts should be made to demonstrate specific in situ hybridization of microbial sequence to areas of tissue pathology and to visible microorganisms or to areas where microorganisms are presumed to be located.
7. These sequence-based forms of evidence for microbial causation should be reproducible.
Once virulent factors have been identified, it is possible to develop a vaccine against the factors. illustrates how the avian flu vaccine was developed using reverse genetic techniques.
For many pathogenic microorganisms, it is not currently possible to apply molecular genetic techniques to a gene in question. Testing a candidate virulence gene requires a relevant animal model of the disease being examined and the ability to genetically manipulate the microorganism that causes the disease. Suitable animal models are lacking for many important human diseases. Additionally, many pathogens cannot be manipulated genetically.
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The spread and severity of infectious disease is influenced by many predisposing factors.
Learning Objectives
• Recognize factors that are classified as predisposing to infectious disease
Key Points
• Some predisposing factors of contracting infectious diseases can be anatomical, genetic, general and disease specific.
• Climate and weather, and other environmental factors that are affected by them, can also predispose people to infectious agents.
• Other factors such as overall health, age and diet are important considerations in the prevention of spreading infectious diseases.
Key Terms
• cystic fibrosis: Cystic fibrosis (also known as CF or mucoviscidosis) is an autosomal recessive genetic disorder that affects most critically the lungs, and also the pancreas, liver and intestine. It is characterized by abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions.
• Chronic granulomatous disease: Also known as CGD, is a diverse group of genetic diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds (most importantly, the superoxide radical) used to kill certain ingested pathogens. This leads to the formation of granulomata (a special type of inflammation) in many organs.
The spread and severity of infectious disease is influenced by many predisposing factors. Some of these are more general and apply to many infectious agents, while others are disease specific. Others can be anatomical. For example, women suffer more frequently from urinary tract infections which can be attributed to their shorter urethra.
Genetics is another contributing factor. Cystic fibrosis is a genetic disease that causes alteration of the mucus in the lungs. This predisposes patients to chronic infections with bacteria which form biofilms in the lungs. The most common infectious agent is Pseudomonas aeruginosa. Another example is chronic granulomatous disease which directly affects the ability of the host immune system to fight invaders.
Climate and weather, and other environmental factors that are affected by them, can also predispose people to infectious agents. A long-standing puzzle has been why flu outbreaks occur seasonally. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Another factor is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus also survives longer on surfaces at colder temperatures and aerosol transmission of the virus is highest in cold environments (less than 5°C) with low relative humidity. Indeed, the lower air humidity in winter seems to be the main cause of seasonal influenza transmission in temperate regions. Some scientists speculate that the seasonal fluctuations of vitamin D levels can be a factor in the spread of influenza too.
Overall health is a very important factor in preventing disease. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other conditions. In general, deliberately-induced immunosuppression is performed to prevent the body from rejecting an organ transplant, treating graft-versus-host disease after a bone marrow transplant, or for the treatment of autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. Of course, the immune system can be weak due to other reasons such as chemotherapy and HIV.
Age is another critical factor. Newborns and infants are more susceptible to infections as are the elderly.
Inadequate diet can raise the risks too. For example, globally, the severe malnutrition common in parts of the developing world causes a large increase in the risk of developing active tuberculosis and other opportunistic infections, due to its damaging effects on the immune system. Along with overcrowding, poor nutrition may contribute to the strong link observed between tuberculosis and poverty. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.03%3A_Disease_Patterns/10.3A%3A_Predisposing_Factors.txt |
After an pathogen invades a host, it undergoes a series of phases that eventually lead to multiplication of the pathogen.
Learning Objectives
• Outline the stages of disease: incubation, prodromal, acute and convalescence periods
Key Points
• The first phase is characterized by complete lack or very few symptoms.
• As the pathogen starts to reproduce actively, the symptoms intensify. Bacterial and viral infections can both cause the same kinds of symptoms but there are some differences too.
• The last phases are characterized by decline in symptoms severity until their disappearance. However, even if the patients recover and return to normal, they may continue to be a source of infection.
Key Terms
• subclinical: Of a disease or injury, without signs and symptoms that are detectable by physical examination or laboratory test; not clinically manifest.
• clinical latency: The period for which an infection is subclinical.
• viral latency: A form of viral dormancy in which the virus does not replicate at all.
Stages of Disease
After an infectious agent invades a host (patient), it undergoes a series of phases (stages) that will eventually lead to its multiplication and release from the host.
STAGE 1: INCUBATION PERIOD
This refers to the time elapsed between exposure to a pathogenic organism, and from when symptoms and signs are first apparent. It may be as short as minutes to as long as thirty years in the case of variant Creutzfeldt–Jakob disease. While the term latency period is used as synonymous, a distinction is sometimes made between incubation period, the period between infection and clinical onset of the disease, and latent period, the time from infection to infectiousness. Whichever is shorter depends on the disease.
A person may be a carrier of a disease, such as Streptococcus in the throat, without exhibiting any symptoms. Depending on the disease, the person may or may not be contagious during the incubation period. During clinical latency, an infection is subclinical. With respect to viral infections, in clinical latency the virus is actively replicating. This is in contrast to viral latency, a form of dormancy in which the virus does not replicate.
STAGE 2: PRODROMAL PERIOD
In this phase, the numbers of the infectious agents start increasing and the immune system starts reacting to them. It is characterized by early symptoms that might indicate the start of a disease before specific symptoms occur. Prodromes may be non-specific symptoms or, in a few instances, may clearly indicate a particular disease. For example fever, malaise, headache and lack of appetite frequently occur in the prodrome of many infective disorders. It also refers to the initial in vivo round of viral replication.
STAGE 3: ACUTE PERIOD
This stage is characterized by active replication or multiplication of the pathogen and its numbers peak exponentially, quite often in a very short period of time. Symptoms are very pronounced, both specific to the organ affected as well as in general due to the strong reaction of the immune system.
Viral infections present with systemic symptoms. This means they involve many different parts of the body or more than one body system at the same time; i.e. a runny nose, sinus congestion, cough, body aches, etc. They can be local at times as in viral conjunctivitis or “pink eye” and herpes. Only a few viral infections are painful, like herpes. The pain of viral infections is often described as itchy or burning.
The classic symptoms of a bacterial infection are localized redness, heat, swelling and pain. One of the hallmarks of a bacterial infection is local pain, pain that is in a specific part of the body. For example, if a cut occurs and is infected with bacteria, pain occurs at the site of the infection. Bacterial throat pain is often characterized by more pain on one side of the throat. An ear infection is more likely to be diagnosed as bacterial if the pain occurs in only one ear.
After the pathogen reaches its peak in newly-produced cells or particles (for viruses), the numbers begin to fall sharply. Symptoms are still present but they are not as strong as in the acute illness phase.
STAGE 4: CONVALESCENCE PERIOD
The patient recovers gradually and returns to normal, but may continue to be a source of infection even if feeling better. In this sense, “recovery” can be considered a synonymous term. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.03%3A_Disease_Patterns/10.3B%3A_Disease_Development.txt |
Once discovered, natural reservoirs elucidate the complete life cycle of infectious diseases, providing effective prevention and control.
Learning Objectives
• Give examples of disease reservoirs and distinguish between common source and propagated outbreaks
Key Points
• Often the natural reservoirs for a human infectious disease are animals such as bats for SARS and rats for plague. Some diseases have no non-human reservoirs: poliomyelitis and smallpox are prominent examples. The natural reservoir of some diseases remains unknown.
• In epidemiology, an epidemic occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience.
• An epidemic may be restricted to one location; however, if it spreads to other countries or continents and affects a substantial number of people, it may be termed a pandemic.
• There are two types of epidemic outbreak: (1) In a common source outbreak, the affected individuals had exposure to a common agent. (2) In a propagated outbreak, the disease spreads person-to-person.
Key Terms
• pandemic: A disease that hits a wide geographical area and affects a large proportion of the population.
• common source outbreak: a type of epidemic outbreak where the affected individuals had an exposure to a common agent.
• propagated outbreak: a type of epidemic outbreak where the disease spreads person-to-person. Affected individuals may become independent reservoirs leading to further exposures.
Disease Reservoirs
A natural reservoir refers to the long-term host of the pathogen of an infectious disease. It is often the case that hosts do not get the disease carried by the pathogen or it is carried as a subclinical infection and so remains asymptomatic and non-lethal.
Once discovered, natural reservoirs elucidate the complete life cycle of infectious diseases, providing effective prevention and control. Some examples of natural reservoirs of infectious diseases include:
• Bubonic plague: marmots, black rats, prairie dogs, chipmunks, and squirrels for bubonic plague
• Chagas disease: armadillos and opossums and several species of New World Leishmania
• Babeiosis and Rocky Mountain spotted fever: ticks
• Colorado tick fever: ground squirrels, porcupines, and chipmunks
• Rabies: raccoons, skunks, foxes, and bats
• Cholera: shellfish
• Severe acute respiratory syndrome (SARS): bats
• Ebola: fruit bats, subhuman primates, and antelope called duikers
Some diseases have no non-human reservoir: poliomyelitis and smallpox are prominent examples. The natural reservoirs of some diseases still remain unknown.
DISEASE EPIDEMICS
In epidemiology, an epidemic occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected, based on recent experience. Epidemiologists often consider the term outbreak to be synonymous to epidemic, but the general public typically perceives outbreaks to be more local and less serious than epidemics.
Epidemics of infectious disease are generally caused by:
• a change in the ecology of the host population (e.g. increased stress or increase in the density of a vector species)
• a genetic change in the parasite population
• the introduction of a new parasite to a host population (by movement of parasites or hosts)
Generally, an epidemic occurs when host immunity to a parasite population is suddenly reduced below that found in the endemic equilibrium and the transmission threshold is exceeded.
An epidemic may be restricted to one location; however, if it spreads to other countries or continents and affects a substantial number of people, it may be termed a pandemic. The declaration of an epidemic usually requires a good understanding of a baseline rate of incidence. Epidemics for certain diseases, such as influenza, are defined as reaching some defined increase in incidence above this baseline.
A few cases of a very rare disease may be classified as an epidemic, while many cases of a common disease (such as the common cold) would not. An epidemic disease is not required to be contagious, and the term has been applied to West Nile fever.
EPIDEMIC OUTBREAKS
There are two types of epidemic outbreaks: (1) In a common source outbreak, the affected individuals had an exposure to a common agent. If the exposure is singular and all of the affected individuals develop the disease over a single exposure and incubation course, it can be termed a point-source outbreak. If the exposure was continuous or variable, it can be termed a continuous outbreak or intermittent outbreak, respectively.
(2) In a propagated outbreak, the disease spreads person-to-person. Affected individuals may become independent reservoirs leading to further exposures. Many epidemics will have characteristics of both common source and propagated outbreaks. For example, secondary person-to-person spread may occur after a common source exposure or environmental vectors may spread a zoonotic disease agent.
The conditions which govern the outbreak of epidemics include infected food supplies, such as drinking water contaminated by waste from people with cholera or typhoid fever or ‘fast food’ products contaminated with salmonella. The migrations of certain animals, such as rats, are in some cases responsible for the spread of plague, from which these animals die in great numbers.
Certain epidemics occur at certain seasons: for example, whooping-cough occurs in spring, whereas measles produces two epidemics – as a rule, one in winter and one in March. Influenza, the common cold, and other infections of the upper respiratory tract, such as sore throat, occur predominantly in the winter.
There is another variation, both as regards the number of persons affected and the number who die in successive epidemics: the severity of successive epidemics rises and falls over periods of five or ten years. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.03%3A_Disease_Patterns/10.3C%3A__Disease_Reservoirs_and_Epidemics.txt |
Defining the means of transmission of a pathogen is important in understanding its biology and in addressing the disease it causes.
Learning Objectives
• Give examples of various modes of transmission, including direct and indirect transmission
Key Points
• Infectious organisms may be transmitted either by direct or indirect contact.
• Transmission may occur through several different mechanisms. Transmission of infectious diseases may also involve a vector. Vectors may be mechanical or biological.
• Pathogens can also be transmitted horizontally or vertically.
Key Terms
• fomite: An inanimate object capable of carrying infectious agents (such as bacteria, viruses and parasites), and thus passively enabling their transmission between hosts.
• aerosolized: Dispersed as an aerosol; particulate.
• vector: A carrier of a disease-causing agent.
For infecting organisms to survive and repeat the infection cycle in other hosts, they (or their progeny) must leave an existing reservoir and cause infection elsewhere. Defining the means of transmission plays an important part in understanding the biology of an infectious agent and in addressing the disease it causes.
Infectious organisms may be transmitted either by direct or indirect contact. Direct contact occurs when an individual comes into contact with the reservoir. Indirect contact occurs when the organism is able to withstand the harsh environment outside the host for long periods of time and still remains infective when specific opportunity arises.
Transmission may occur through several different mechanisms. Respiratory diseases and meningitis are commonly acquired by contact with aerosolized droplets, spread by sneezing, coughing, talking, kissing, or even singing. Gastrointestinal diseases are often acquired by ingesting contaminated food and water. Washing hands is an effective measure to prevent contaminating food and water. A common method of transmission in under-developed countries is fecal-oral transmission. In such cases, sewage water is used to wash food or is consumed. Sexually transmitted diseases are acquired through contact with bodily fluids, generally as a result of sexual activity. Some infectious agents may be spread as a result of contact with a contaminated, inanimate object (known as a fomite), such as a coin passed from one person to another, while other diseases penetrate the skin directly.
Transmission of infectious diseases may also involve a vector. Vectors may be mechanical or biological. A mechanical vector picks up an infectious agent on the outside of its body and transmits it in a passive manner. An example of a mechanical vector is a housefly, which lands on cow dung, contaminating its appendages with bacteria from the feces and then lands on food. The pathogen never enters the body of the fly.
In contrast, biological vectors harbor pathogens within their bodies and deliver pathogens to new hosts in an active manner, usually a bite. Biological vectors are often responsible for serious blood-borne diseases, such as malaria, viral encephalitis, Chagas disease, Lyme disease, and African sleeping sickness. Biological vectors are usually, though not exclusively, arthropods, such as mosquitoes, ticks, fleas, and lice. Vectors are often required in the life cycle of a pathogen. A common strategy used to control vector borne infectious diseases is to interrupt the life cycle of a pathogen by killing the vector.
All of the above modes are examples of horizontal transmission because the infecting organism is transmitted from person to person in the same generation. There are also a variety of infections transmitted vertically, that is from mother to child during the birthing process or fetal development. Common disorders transmitted this way include AIDs, hepatitis, herpes, and cytomegalovirus. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.03%3A_Disease_Patterns/10.3D%3A_Infectious_Disease_Transmission.txt |
Pathogens have evolved to adapt to their environment and their host in order to survive.
Learning Objectives
• Discuss the contributing factors to pathogen evolution
Key Points
• Ecological competence is the ability of an organism, often a pathogen, to survive and compete in new habitats.
• Epidemiology is another important tool used to study disease in a population.
• In most cases, microorganisms live in harmony with their hosts via mutual or commensal interactions.
• Diseases can emerge when existing parasites become pathogenic or when new pathogenic parasites enter a new host.
Key Terms
• zoonose: Infectious diseases transmitted between different species of animals, usually from a vertebrate animal to a human
• ecological competence: The ability of an organism, often a pathogen, to survive and compete in new habitats.
• virulence: The degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host and it is determined by virulence factors.
Ecological competence is the ability of an organism, often a pathogen, to survive and compete in new habitats. If a pathogen does not have this, it will likely become extinct. In the case of plant pathogens, it is also their ability to survive between growing seasons. For example, peanut clump virus can survive in the spores of its fungal vector until a new growing season begins and it can proceed to infect its primary host again.
Epidemiology is another important tool used to study disease in a population. For infectious diseases, it helps to determine if a disease outbreak is sporadic (occasional occurrence), endemic (regular cases often occurring in a region), epidemic (an unusually high number of cases in a region), or pandemic (a global epidemic). The Black Death (plague) of the 14th century reduced the world population from an estimated 450 million to 350 – 375 million.
In most cases, microorganisms live in harmony with their hosts via mutual or commensal interactions. Diseases can emerge when existing parasites become pathogenic or when new pathogenic parasites enter a new host. Coevolution between parasite and host can lead to hosts becoming resistant to the parasites or the parasites may evolve greater virulence, leading to immunopathological disease.
In addition, human activity is involved with many emerging infectious diseases, such as environmental change enabling a parasite to occupy new niches. When that happens, a pathogen that had been confined to a remote habitat has a wider distribution and possibly, a new host organism. Diseases transferred from nonhuman to human hosts are known as zoonoses.
Under disease invasion, when a parasite invades a new host species, it may become pathogenic in the new host. Several human activities have led to the emergence and spread of new diseases, such as encroachment on wildlife habitats, changes in agriculture, the destruction of rain forests, uncontrolled urbanization, modern transport.
According to evolutionary medicine, virulence increases with horizontal transmission (between non-relatives) and decreases with vertical transmission (from parent to child). Optimal virulence is a concept relating to the ecology of hosts and parasites. One definition of this is the host’s parasite-induced loss of fitness. The parasite’s fitness is determined by its success in transmitting its offspring to other hosts.
At one stage, the consensus was that over time, virulence moderated and parasitic relationships evolved toward symbiosis. This view has been challenged. A pathogen that is too restrained will lose out in competition to a more aggressive strain that diverts more host resources to its own reproduction. However, the host, being the parasite’s resource and habitat in a way, suffers from this higher virulence. This might induce faster host death, and act against the parasite’s fitness by reducing probability to encounter another host (killing the host too fast to allow for transmission).
Thus, there is a natural force providing pressure on the parasite to “self-limit” its virulence. The idea is then, that there exists an equilibrium point of virulence, where parasite’s fitness is highest. Any movement on the virulence axis, towards higher or lower virulence, will result in lower fitness for the parasite, and this will be selected against. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.03%3A_Disease_Patterns/10.3E%3A_Ecology_Epidemiology_and_Evolution_of_Pathogens.txt |
Working with microorganisms, especially pathogens, requires special equipment and safety practices.
Learning Objectives
• Distinguish between the different biohazard levels 1, 2, 3 and 4
Key Points
• The CDC categorizes various diseases in levels of biohazard: Level 1 being minimum risk and Level 4 being extreme risk.
• BSL-1 lab is used to perform research mostly on noninfectious microbes using standard equipment and routine lab safety procedures.
• BSL-2 work is performed with bacteria and viruses that cause only mild disease to humans, or are difficult to contract via aerosol in a lab setting. Safety regulations are stricter.
• In a BSL-3 setting, the work is with bacteria and viruses that can cause severe to fatal disease in humans, but for which vaccines or other treatments exist. The laboratory has special engineering and design features.
• BSL-4 level is mandatory for research on viruses and bacteria that cause severe to fatal disease in humans, and for which no vaccines or treatments are available. The use of a positive-pressure personnel suit is mandatory as well as many additional safety measures of the labs.
Key Terms
• biohazards: Biological substances that pose a threat to the health of living organisms, especially humans.
Keeping Safe in the Laboratory
Working with microorganisms, especially pathogens, requires special equipment and safety practices. Biological hazards, also known as biohazards, refer to biological substances that pose a threat to the health of living organisms, especially humans. The biohazard symbol is used in the labeling of biological materials that carry a significant health risk, including viral samples and used hypodermic needles.
The United States’ Centers for Disease Control and Prevention (CDC) categorize various diseases in levels of biohazard: Level 1 being minimum risk and Level 4 being extreme risk. Laboratories and other facilities are categorized as BSL (Biosafety Level) 1-4 or as P1 through P4 for short (Pathogen or Protection Level).
BIOHAZARD LEVEL 1:
Bacteria and viruses including Bacillus subtilis, Escherichia coli , canine hepatitis, varicella (chicken pox), as well as some cell cultures and non- infectious bacteria. Work is generally conducted on open bench tops using standard microbiological practices. At this level, precautions against the biohazardous materials in question are minimal, most likely involving gloves and some sort of facial protection. Decontamination procedures are similar in most respects to modern precautions against everyday microorganisms (i.e., washing one’s hands with anti-bacterial soap, washing all exposed surfaces of the lab with disinfectants, etc.). In a lab environment all materials used for cell and/or bacteria cultures are decontaminated via autoclave. Laboratory personnel have specific training in the procedures conducted in the laboratory and are supervised by a scientist with general training in microbiology or a related science.
BIOHAZARD LEVEL 2:
Bacteria and viruses that cause only mild disease to humans, or are difficult to contract via aerosol in a lab setting, such as hepatitis A, B, and C, influenza A, Lyme disease, salmonella, mumps, measles, scrapie, dengue fever, and HIV. BSL-2 differs from BSL-1 in that:
• laboratory personnel have specific training in handling pathogenic agents and are directed by scientists with advanced training;
• access to the laboratory is limited when work is being conducted;
• extreme precautions are taken with contaminated sharp items;
• certain procedures in which infectious aerosols or splashes may be created are conducted in biological safety cabinets or other physical containment equipment.
BIOHAZARD LEVEL 3:
Bacteria and viruses that can cause severe to fatal disease in humans, but for which vaccines or other treatments exist, such as anthrax, West Nile virus, Venezuelan equine encephalitis, SARS virus, tuberculosis, typhus, Rift Valley fever, Rocky Mountain spotted fever, yellow fever, and malaria. Among parasites Plasmodium falciparum, which causes malaria, and Trypanosoma cruzi, which causes trypanosomiasis (sleeping sickness), also come under this level.
Laboratory personnel have specific training in handling pathogenic and potentially lethal agents, and are supervised by competent scientists experienced in working with these agents. All procedures involving the manipulation of infectious materials are conducted within biological safety cabinets, specially designed hoods, or other physical containment devices, or by personnel wearing appropriate protective clothing and equipment. The laboratory has special engineering and design features.
BIOHAZARD LEVEL 4:
Viruses and bacteria that cause severe to fatal disease in humans, and for which vaccines or other treatments are not available, such as Bolivian and Argentine hemorrhagic fevers, Dengue hemorrhagic fever, Marburg virus, Ebola virus, hantaviruses, Lassa fever virus, Crimean-Congo hemorrhagic fever, and other hemorrhagic diseases. Variola virus (smallpox) is an agent that is worked with at BSL-4 despite the existence of a vaccine.
When dealing with biological hazards at this level the use of a positive-pressure personnel suit, with a segregated air supply, is mandatory. The entrance and exit of a Level Four biolab will contain multiple showers, a vacuum room, an ultraviolet-light room, autonomous detection system, and other safety precautions designed to destroy all traces of the biohazard. All air and water services going to and coming from a Biosafety Level 4 (P4) lab will undergo similar decontamination procedures to eliminate the possibility of an accidental release. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.03%3A_Disease_Patterns/10.3F%3A__Safety_in_the_Microbiology_Laboratory.txt |
The index case is identified in epidemiology studies by tracking down the infected patients to try to determine how the disease originated.
Learning Objectives
• Describe the concept of patient zero or the index case
Key Points
• The index or primary case is the initial patient in the population of an epidemiological investigation. It may indicate the source of the disease, the possible spread, and which reservoir holds the disease in-between outbreaks.
• In the early years of the AIDS epidemic, there was controversy about a so-called Patient Zero, who was the basis of a complex transmission scenario.
• Other prominent “Patient Zeroes” include Typhoid Mary.
Key Terms
• “Patient Zero”: A term used to refer to the index case in the spread of HIV in North America.
• epidemiology: The branch of a science dealing with the spread and control of diseases, computer viruses, concepts, etc., throughout populations or systems.
The index or primary case is the initial patient in the population of an epidemiological investigation. The index case may indicate the source of the disease, the possible spread, and which reservoir holds the disease in-between outbreaks. The index case is the first patient that indicates the existence of an outbreak. Earlier cases may be found and are labeled primary, secondary, tertiary, etc.
“Patient Zero” was used to refer to the index case in the spread of HIV in North America. The index case is identified in epidemiology studies by tracking down the infected patients to try to determine how the disease originated.
For example, in the early years of the AIDS epidemic there was controversy about a so-called Patient Zero, who was the basis of a complex transmission scenario. This epidemiological study showed how Patient Zero had infected multiple partners with HIV, and they in turn transmitted it to others and rapidly spread the virus to locations all over the world.
The CDC identified Gaëtan Dugas as the first person to bring HIV from Africa to the United States and to introduce it to gay bathhouses. Dugas was a flight attendant who was sexually promiscuous in several North American cities. He was vilified for several years as a “mass spreader” of HIV, and seen as the original source of the HIV epidemic among homosexual men. Later, the study’s methodology and conclusions representation were repudiated.
A 2007 study published in the Proceedings of the National Academy of Sciences claimed that, based on the results of genetic analysis, current North American strains of HIV probably moved from Africa to Haiti and then entered the United States around 1969, probably through a single immigrant. However, the immigrant died in St. Louis, Missouri of complications from AIDS in 1969, and most likely became infected in the 1950s, so there were prior carriers of HIV strains in North America.
Ebola
In the eboloa outbreak of 2014, the Patient Zero was identified as a two year-old boy in Guinea who died on Dec. 2, 2013 of Ebolavirus during the fruitbat migration. His sister and mother and grandmother then died. Visitors from other villages came to pay their respects and tragically carried the virus back with them. As of November 2014, about 5,500 people had died of Ebolavirus.
Typhoid Mary
Other prominent “Patient Zeroes” include Typhoid Mary. She was the first person in the United States identified as an asymptomatic carrier of the pathogen associated with typhoid fever. She was presumed to have infected some 51 people, three of whom died, over the course of her career as a cook. She was forcibly isolated twice by public health authorities and died after a total of nearly three decades in isolation.
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A nosocomial infection is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is sometimes instead called a health care–associated infection. Such an infection can be acquired in hospital, nursing home, rehabilitation facility, outpatient clinic, or other clinical settings. Infection is spread to the susceptible patient in the clinical setting by various means.
10.04: Nosocomial Infections
Nosocomial infections can cause severe pneumonia and infections of the urinary tract, bloodstream, and other parts of the body.
Learning Objectives
• Give examples of hospital-acquired infections (HAI) or nosocomial infections
Key Points
• Some well known nosocomial infections include: ventilator-associated pneumonia, Methicillin resistant Staphylococcus aureus, Candida albicans, Acinetobacter baumannii, Clostridium difficile, Tuberculosis, Urinary tract infection, Vancomycin-resistant Enterococcus and Legionnaires’ disease.
• Methicillin-resistant Staphylococcus aureus ( MRSA ) is a bacterium responsible for several difficult-to-treat infections in humans.
• Hospital acquired pneumonia is the second most common nosocomial infection (urinary tract infection is the most common) and accounts for 15-20% of the total.
Key Terms
• nosocomial infection: an infection whose development is favoured by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff
• MRSA: Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus (ORSA).
• pneumonia: An acute or chronic inflammation of the lungs caused by viruses, bacteria or other microorganisms, or sometimes by physical or chemical irritants.
• nosocomial: A nosocomial infection, also known as a hospital-acquired infection or HAI, is an infection whose development is favoured by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff.
A nosocomial infection, also known as a hospital-acquired infection or HAI, is an infection whose development is favoured by a hospital environment, such as one acquired by a patient during a hospital visit, or one developed among hospital staff. Such infections include fungal and bacterial infections, and are aggravated by the reduced resistance of individual patients.
In the United States, the Centers for Disease Control and Prevention estimated roughly 1.7 million hospital-associated infections, from all types of microorganisms (including bacteria), cause or contribute to 99,000 deaths each year. In Europe, where hospital surveys have been conducted, the category of Gram-negative infections are estimated to account for two-thirds of the 25,000 deaths each year. Nosocomial infections can cause severe pneumonia and infections of the urinary tract, bloodstream, and other parts of the body. Many types are difficult to attack with antibiotics, and antibiotic resistance is spreading to Gram-negative bacteria that can infect people outside the hospital.
Known nosocomial infections include:
• Ventilator-associated pneumonia
• Staphylococcus aureus
• Methicillin resistant Staphylococcus aureus
• Candida albicans
• Pseudomonas aeruginosa
• Acinetobacter baumannii
• Stenotrophomonas maltophilia
• Clostridium difficile
• Tuberculosis
• Urinary tract infection
• Hospital-acquired pneumonia
• Gastroenteritis
• Vancomycin-resistant Enterococcus
• Legionnaires’ disease.
Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus (ORSA). MRSA is any strain of Staphylococcus aureus that has developed resistance to beta-lactam antibiotics, which include the penicillins (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalosporins. Strains unable to resist these antibiotics are classified as methicillin-sensitive Staphylococcus aureus, or MSSA. The development of such resistance does not cause the organism to be more intrinsically virulent than strains of Staphylococcus aureus that have no antibiotic resistance, but resistance does make MRSA infection more difficult to treat with standard types of antibiotics, and thus more dangerous.
Hospital-acquired pneumonia (HAP), or nosocomial pneumonia, refers to any pneumonia contracted by a patient in a hospital at least 48-72 hours after being admitted. It is usually caused by a bacterial infection, rather than a virus. HAP is the second most common nosocomial infection (urinary tract infection is the most common), and accounts for 15-20% of the total. It is the most common cause of death among nosocomial infections, and is the primary cause of death in intensive care units. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.04%3A_Nosocomial_Infections/10.4A%3A_Microorganisms_in_the_Hospital.txt |
Numerous risk factors in the hospital setting can predispose a patient to infection.
Learning Objectives
• Discuss the risk factors that contribute to the acquiring of nosocomial infections or hospital-acquired infections
Key Points
• People in hospitals are usually already in a “poor state of health,” impairing their defense against bacteria.
• Invasive devices bypass the body’s natural lines of defense against pathogens and provide an easy route for infection.
• Patients’ treatments can leave them vulnerable to infection.
Key Terms
• infection: An uncontrolled growth of harmful microorganisms in a host.
• defense: The action of defending or protecting from attack, danger, or injury.
• Invasive: Invasive species, also called invasive exotics or simply exotics, is a nomenclature term and categorization phrase used for flora and fauna, and for specific restoration-preservation processes in native habitats, with several definitions.
Susceptible Hosts
A nosocomial infection, also known as a hospital-acquired infection or HAI, is an infection whose development is favoured by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff. Such infections include fungal and bacterial infections. They are aggravated by the reduced resistance of individual patients. Numerous risk factors in the hospital setting predispose a patient to infection. These risk factors can broadly be divided into three areas.
• People in hospitals are usually already in a ‘poor state of health’, impairing their defense against bacteria. Advanced age or premature birth, along with immunodeficiency (due to drugs, illness, or irradiation) present a general risk, while other diseases can present specific risks; for instance, chronic obstructive pulmonary disease can increase chances of respiratory tract infection.
• Invasive devices, for instance intubation tubes, catheters, surgical drains, and tracheostomy tubes all bypass the body’s natural lines of defense against pathogens and provide an easy route for infection. Patients already colonized at the time of admission are instantly put at greater risk when they undergo invasive procedures.
• Patients’ treatments can leave them vulnerable to infection: immunosuppression and antacid treatment undermine the body’s defences, while antimicrobial therapy (removing competitive flora and only leaving resistant organisms) and recurrent blood transfusions have also been identified as risk factors.
Prevention
Hospitals have sanitation protocols regarding uniforms, equipment sterilization, washing, and other preventive measures. Thorough hand washing and/or use of alcohol rubs by all medical personnel before and after each patient contact is one of the most effective ways to combat nosocomial infections. More careful use of antimicrobial agents, such as antibiotics, is also considered vital. Despite sanitation protocol, patients cannot be entirely isolated from infectious agents. Furthermore, patients are often prescribed antibiotics and other antimicrobial drugs to help treat illness; this can increase the selection pressure for the emergence of resistant strains.
10.4C: Chain of Transmission
Learning Objectives
• Differentiate between the various types of transmission: air-borne, common vehicle, vector borne, direct and indirect contact transmission
The drug-resistant Gram-negative bacteria, for the most part, threaten only hospitalized patients whose immune systems are weak. They can survive for a long time on surfaces in the hospital and they enter the body through wounds, catheters, and ventilators.
The most important and frequent mode of transmission of nosocomial infections is by direct contact. Transmission occurs when droplets containing microbes from the infected person are propelled a short distance through the air and deposited on the host’s body; droplets are generated from the source person mainly by coughing, sneezing, and talking, and during the performance of certain procedures, such as bronchoscopy.
Dissemination can be either airborne droplet nuclei (small-particle residue {5 µm or smaller in size} of evaporated droplets containing microorganisms that remain suspended in the air for long periods of time) or dust particles containing the infectious agent. Microorganisms carried in this manner can be dispersed widely by air currents and may become inhaled by a susceptible host within the same room or over a longer distance from the source patient, depending on environmental factors; therefore, special air-handling and ventilation are required to prevent airborne transmission. Microorganisms transmitted by airborne transmission include Legionella, Mycobacterium tuberculosis and the rubeola and varicella viruses.
Common vehicle transmission applies to microorganisms transmitted to the host by contaminated items, such as food, water, medications, devices, and equipment. Vector borne transmission occurs when vectors such as mosquitoes, flies, rats, and other vermin transmit microorganisms.
Contact transmission is divided into two subgroups: direct-contact transmission and indirect-contact transmission.
Direct-contact transmission involves a direct body surface-to-body surface contact and physical transfer of microorganisms between a susceptible host and an infected or colonized person, such as when a person turns a patient, gives a patient a bath, or performs other patient-care activities that require direct personal contact. Direct-contact transmission can also occur between two patients, with one serving as the source of the infectious microorganisms and the other as a susceptible host.
Indirect-contact transmission involves contact of a susceptible host with a contaminated intermediate object, usually inanimate, such as contaminated instruments, needles, or dressings, or contaminated gloves that are not changed between patients. In addition, the improper use of saline flush syringes, vials, and bags has been implicated in disease transmission in the US, even when healthcare workers had access to gloves, disposable needles, intravenous devices, and flushes.
Key Points
• Contact transmission is divided into two subgroups: direct-contact transmission and indirect-contact transmission.
• Direct-contact transmission involves a direct body surface-to-body surface contact and physical transfer of microorganisms.
• Indirect-contact transmission involves contact of a susceptible host with a contaminated intermediate object, usually inanimate.
Key Terms
• microorganisms: A microorganism or microbe is a microscopic organism that comprises either a single cell (unicellular), cell clusters, or multicellular relatively complex organisms.
• susceptible: likely to be affected by something; here, sensitive to growth inhibition by an antimicrobial drug.
• transmission: Transmission is the passing of a communicable disease from an infected host individual or group to a conspecific individual or group, regardless of whether the other individual was previously infected. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.04%3A_Nosocomial_Infections/10.4B%3A_Compromised_Host.txt |
Learning Objectives
• Give examples of ways nosocomial infections can be controlled or prevented
Hospitals have sanitation protocols regarding uniforms, equipment sterilization, washing, and other preventive measures. Thorough hand washing and/or the use of alcohol rubs by all medical personnel before and after each patient contact is one of the most effective ways to combat nosocomial infections. More careful use of antimicrobial agents, such as antibiotics, is also considered vital.
Despite sanitation protocol, patients cannot be entirely isolated from infectious agents. Furthermore, patients are often prescribed antibiotics and other antimicrobial drugs to help treat illness; this may increase the selection pressure for the emergence of resistant strains. Sterilization goes further than just sanitizing. It kills all microorganisms on equipment and surfaces through exposure to chemicals, ionizing radiation, dry heat, or steam under pressure. Isolation precautions are designed to prevent transmission of microorganisms by common routes in hospitals. Because agent and host factors are more difficult to control, interruption of transfer of microorganisms is directed primarily at transmission.
The Importance of Handwashing
Handwashing is the single most important measure to reduce the risks of transmitting skin microorganisms from one person to another or from one site to another on the same patient. Washing hands as promptly and thoroughly as possible between patient contacts and after contact with blood, body fluids, secretions, excretions, and equipment or articles contaminated by them is an important component of infection control and isolation precautions.
The spread of nosocomial infections among immunocompromised patients is connected with health care workers’ hand contamination in almost 40% of cases. This presents a challenging problem in the modern hospitals. The best way for workers to overcome this problem is by conducting correct hand- hygiene procedures; this is why in 2005 the WHO launched the GLOBAL Patient Safety Challenge.
Two categories of micro-organisms can be present on health care workers’ hands: transient flora and resident flora. The first is represented by the micro-organisms taken by workers from the environment, and the bacteria in it. These are often capable of surviving on the human skin and sometimes to grow. The second group is represented by the permanent micro-organisms living on the skin surface, on the stratum corneum or immediately under it. They are capable of surviving on the human skin and of growing freely on it. They have low pathogenicity and infection rate, and they create a kind of protection from the colonization from other more pathogenic bacteria.
The skin of workers is colonized by 3.9 x 104 – 4.6 x 106 cfu/cm2. The microbes comprising the resident flora are: Staphylococcus epidermidis, S. hominis, and Microccocus, Propionibacterium, Corynebacterium, Dermobacterium, and Pitosporum spp., while in the transitional could be found S. aureus, and Klebsiella pneumoniae, and Acinetobacter, Enterobacter and Candida spp. The goal of hand hygiene is to eliminate the transient flora with a careful and proper performance of hand washing, using different kinds of soap, both normal and antiseptic, and alcohol-based gels. The main problems found in the practice of hand hygiene are connected with the lack of available sinks and the time-consuming performance of hand washing. An easy way to resolve this problem could be the use of alcohol-based hand rubs, because of faster application compared to correct hand washing.
The Second Line of Defense: Gloves
Gloves play an important role in reducing the risks of transmission of microorganisms. Gloves are worn for three important reasons in hospitals.
• They are worn to provide a protective barrier and to prevent gross contamination of the hands when touching blood, body fluids, secretions, excretions, mucous membranes, and non-intact skin. In the USA, the Occupational Safety and Health Administration (OSHA) has mandated wearing gloves to reduce the risk of blood-borne pathogen infections.
• Gloves are worn to reduce the likelihood microorganisms present on the hands of personnel will be transmitted to patients during invasive or other patient-care procedures that involve touching a patient’s mucous membranes and nonintact skin.
• They are worn to reduce the likelihood the hands of personnel contaminated with micro-organisms from a patient or a fomite (contaminated object) can be transmitted to another patient. In this situation, gloves must be changed between patient contacts, and hands should be washed after gloves are removed.
Surfaces
Sanitizing surfaces is an often overlooked, yet crucial, component of the strategy for the cycle of infection in health care environments. Modern sanitizing methods such as NAV-CO2 have been effective against gastroenteritis, MRSA, and influenza agents. Use of hydrogen peroxide vapor has been clinically proven to reduce infection rates and risk of acquisition. Hydrogen peroxide is effective against endospore-forming bacteria, such as Clostridium difficile, where alcohol has been shown to be ineffective.
Microorganisms are known to survive on inanimate “touch” surfaces for extended periods of time. This can be especially troublesome in hospital environments, where patients with immunodeficiencies are at enhanced risk for contracting nosocomial infections.
Wearing an apron during patient care reduces the risk of infection. The apron should either be disposable or be used only when caring for a specific patient.
Key Points
• Handwashing frequently is called the single most important measure to reduce the risks of transmitting skin microorganisms from one person to another or from one site to another on the same patient.
• Thorough hand washing and/or use of alcohol rubs by all medical personnel before and after each patient contact is one of the most effective ways to combat nosocomial infections.
• Sanitizing surfaces is an often overlooked, yet crucial, component of breaking the cycle of infection in health care environments.
Key Terms
• sterilization: Any process that eliminates or kills all forms of microbial life present on a surface, solution, or solid compound.
• nosocomial: contracted in a hospital, or arising from hospital treatment
• sanitation: The policy and practice of protecting health through hygienic measures.
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Epidemiology is the study and analysis of the distribution (who, when, and where) and determinants of health and disease conditions in defined populations.
10.05: Epidemiology and Public Health
Descriptive epidemiology focuses on describing disease distribution by characteristics relating to time, place, and people.
Learning Objectives
• Describe the role of a descriptive epidemiology
Key Points
• Epidemiology is the science concerned with the study of the factors that influence and determine the frequency and distribution of disease, injury, and other health -related events and their causes in a defined human population.
• The more fully a descriptive epidemiologist can describe people, places and times, and any correlations between the three, the more likely it is that patterns will emerge which can be considered as risk factors for certain kinds of health issues.
• Epidemiologists use data as an information source for communicating information to people and to influence public policy.
Key Terms
• socioeconomic: Of or pertaining to social and economic factors.
• epidemiology: The branch of a science dealing with the spread and control of diseases, computer viruses, concepts, etc., throughout populations or systems.
• risk factor: A variable associated with an increased risk of disease or infection.
The goal of epidemiology is to establish causal factors for health issues in order to improve the health and safety of entire populations. A population can refer to a town, country, age group, or race. Health issues refer to anything that might impact health in the present or future. For epidemiologists, data on who is most likely to be injured in car crashes can be just as valuable as a topic of inquiry as data on what part of the population is most at risk for developing complications from the flu. In order to accomplish this, epidemiology has two main branches: descriptive and analytical.
Descriptive epidemiology evaluates and catalogs all the circumstances surrounding a person affected by a health event of interest. Analytical epidemiologists use data gathered by descriptive epidemiology experts to look for patterns suggesting causation. The end goal of both branches is to reduce the incidence of health events or diseases by understanding the risk factors for the health events or diseases. Both descriptive and analytical epidemiology often serve public health organizations by providing information that may reduce disease or reduce other kinds of events that impact people’s health.
The primary considerations for descriptive epidemiology are frequency and pattern. Frequency evaluates the rate of occurrence, and pattern helps analytical epidemiologists suggest risk factors. Descriptive epidemiology evaluates frequency and pattern by examining the person, place, and time in relationship to health events.
Descriptive epidemiology examines factors like age, education, socioeconomic status, availability of health services, race, and gender. Evaluations of specific individuals may also include gathering information on behaviors like drug abuse, shift work, eating, and exercise patterns.
10.5B: Analytical Epidemiology
Epidemiology draws statistical inferences, mostly about causes of disease in populations based on available samples of it.
Learning Objectives
• Describe the role of an analytical epidemiologist
Key Points
• Epidemiologists employ a range of study designs from the observational to experimental and they are generally categorized as descriptive, analytic, and experimental.
• Analytic epidemiology aims to further examine known associations or hypothesized relationships.
• Analytical observations deal more with the ‘how’ of a health -related event.
Key Terms
• analytical: pertaining to or emanating from analysis.
• epidemiology: Epidemiology is the study (or the science of the study) of the patterns, causes, and effects of health and disease conditions in defined populations.
Epidemiology is the study (or the science of the study) of the patterns, causes, and effects of health and disease conditions in defined populations. It is the cornerstone of public health, and informs policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive medicine. Epidemiologists help with study design, collection and statistical analysis of data, and interpretation and dissemination of results (including peer review and occasional systematic review). Epidemiology has helped develop methodology used in clinical research, public health studies and, to some extent, basic research in the biological sciences.
Epidemiologists employ a range of study designs from observational to experimental and generally categorized as descriptive, analytic (aiming to further examine known associations or hypothesized relationships), and experimental (a term often equated with clinical or community trials of treatments and other interventions).
Where descriptive epidemiology describes occurrence of disease (or of its determinants) within a population, the analytical epidemiology aims to gain knowledge on the quality and the amount of influence that determinants have on the occurrence of disease. The usual way to gain this knowledge is by group comparisons. Such a comparison starts from one or more hypotheses about how the determinant may influence occurrence of disease. Analytical epidemiology attempts to determine the cause of an outbreak. Using the case control method, the epidemiologist can look for factors that might have preceded the disease. Often, this entails comparing a group of people who have the disease with a group that is similar in age, sex, socioeconomic status, and other variables, but does not have the disease. In this way, other possible factors, e.g., genetic or environmental, might be identified as factors related to the outbreak. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.05%3A_Epidemiology_and_Public_Health/10.5A%3A_Descriptive_Epidemiology.txt |
Experimental epidemiology uses an experimental model to confirm a causal relationship suggested by observational studies.
Learning Objectives
• Summarize the purpose of experimental epidemiology and the three case types: randomized control, field and community trial
Key Points
• Experimental epidemiology is the study of the relationships of various factors determining the frequency and distribution of diseases in a community.
• Experimental epidemiology contains three case types: randomized control trial (often used for new medicine or drug testing), field trial (conducted on those at a high risk of conducting a disease), and community trial (research on social originating diseases).
• The method employs prospective population experiments designed to test epidemiological hypotheses, and usually attempt to relate the postulated cause to the observed effect. Trials of new anthelmintics are an example.
Key Terms
• epidemiology: Epidemiology is the study (or the science of the study) of the patterns, causes, and effects of health and disease conditions in defined populations.
• Experimental: An experiment is a methodical procedure carried out with the goal of verifying, falsifying, or establishing the validity of a hypothesis.
• statistical: of or pertaining to statistics
Epidemiology is the study (or the science of the study) of the patterns, causes, and effects of health and disease conditions in defined populations. It is the cornerstone of public health, and informs policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive medicine. Epidemiologists help with study design, collection and statistical analysis of data, and interpretation and dissemination of results (including peer review and occasional systematic review). Epidemiology has helped develop methodology used in clinical research, public health studies and, to a lesser extent, basic research in the biological sciences.
Epidemiologists employ a range of study designs from the observational to experimental and they are generally categorized as descriptive, analytic (aiming to further examine known associations or hypothesized relationships), and experimental (a term often equated with clinical or community trials of treatments and other interventions). In observational studies, nature is allowed to “take its course”, as epidemiologists observe from the sidelines. Controversially, in experimental studies, the epidemiologist is the one in control of all of the factors entering a certain case study. Epidemiological studies are aimed, where possible, at revealing unbiased relationships between exposures such as alcohol or smoking, biological agents, stress, or chemicals to mortality or morbidity. The identification of causal relationships between these exposures and outcomes is an important aspect of epidemiology. Modern epidemiologists use informatics as a tool.
Experimental epidemiology contains three case types: randomized control trial (often used for new medicine or drug testing), field trial (conducted on those at a high risk of conducting a disease), and community trial (research on social originating diseases). Experimental epidemiology tests a hypothesis about a disease or disease treatment in a group of people. This strategy might be used to test whether or not a particular antibiotic is effective against a particular disease-causing organism. One group of infected individuals is divided randomly so that some receive the antibiotic and others receive a placebo—a “false” drug that is not known to have any medical effect. In this case, the antibiotic is the variable, i.e., the experimental factor being tested to see if it makes a difference between the two otherwise similar groups. If people in the group receiving the antibiotic recover more rapidly than those in the other group, it may logically be concluded that the variable—antibiotic treatment—made the difference. Thus, the antibiotic is said to be effective.
Although epidemiology is sometimes viewed as a collection of statistical tools used to elucidate the associations of exposures to health outcomes, a deeper understanding of this science is that of discovering causal relationships. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.05%3A_Epidemiology_and_Public_Health/10.5C%3A_Experimental_Epidemiology.txt |
Promotion of hand washing, breastfeeding, delivery of vaccinations, and distribution of condoms are examples of public health measures.
Learning Objectives
• Give examples of common public health measures that are recommended to control the spread of disease
Key Points
• Hand washing for hand hygiene is the act of cleaning the hands with or without the use of water or another liquid, or with the use of soap, for the purpose of removing soil, dirt, and/or microorganisms.
• Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts (i.e., via lactation) rather than from a baby bottle or other container.
• Vaccination is the administration of antigenic material (a vaccine ) to stimulate an individual’s immune system to develop adaptive immunity to a pathogen.
Key Terms
• hygiene: Those conditions and practices that promote and preserve health.
• immunity: the state of being insusceptible to a specific thing.
• vaccination: inoculation with a vaccine in order to protect a particular disease or strain of disease.
Public Health Measures
The focus of public health intervention is to improve health and quality of life through the prevention and treatment of disease and other physical and mental health conditions. This can be done through surveillance of cases, and the promotion of healthy behaviors. Promotion of hand washing and breastfeeding, delivery of vaccinations, and distribution of condoms to control the spread of sexually transmitted diseases, are examples of common public health measures.
HAND WASHING
Hand washing for hand hygiene is the act of cleaning the hands with or without the use of water or another liquid, or with the use of soap, for the purpose of removing soil, dirt, and/or microorganisms. Medical hand hygiene pertains to the hygiene practices related to the administration of medicine and medical care that prevents or minimizes disease and the spreading of disease. The main medical purpose of washing hands is to cleanse the hands of pathogens (including bacteria or viruses) and chemicals, which can cause personal harm or disease. This is especially important for people who handle food or work in the medical field, but it is also an important practice for the general public. People can become infected with respiratory illnesses, such as influenza or the common cold; for example, if they don’t wash their hands before touching their eyes, nose, or mouth. Indeed, the Centers for Disease Control and Prevention (CDC) has stated: “It is well documented that one of the most important measures for preventing the spread of pathogens is effective hand washing. ”
As a general rule, however, handwashing protects people poorly or not at all from droplet- and airborne diseases, such as measles, chickenpox, influenza, and tuberculosis. It protects best against diseases transmitted through fecal-oral routes (such as many forms of stomach flu) and direct physical contact (such as impetigo). In addition to hand washing with soap and water, the use of alcohol gels is another form of killing some kinds of pathogens and healthful bacteria, but their effectiveness is disputed, and may lead to antibiotica-resistant bacterial strains.
BREASTFEEDING
Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts (i.e., via lactation) rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk. It is recommended that mothers breastfeed for six months or more, without the addition of infant formula or solid food. After the addition of solid food, mothers are advised to continue breastfeeding for at least a year, and can continue for two years or more. Human breast milk is the healthiest form of milk for babies. There are few exceptions, such as when the mother is taking certain drugs or is infected with human T-lymphotropic virus, or has active untreated tuberculosis. Maternal HIV infection is always an absolute contraindication to breastfeeding in developed countries with access to infant formula and clean drinking water (regardless of maternal HIV viral load or antiretroviral treatment) due to the risk for mother to child HIV transmission. Breastfeeding promotes health and helps to prevent disease. Artificial feeding is associated with more deaths from diarrhea in infants in both developing and developed countries. Experts agree that breastfeeding is beneficial, and have concerns about artificial formulas but there are conflicting views about how long exclusive breastfeeding remains beneficial.
VACCINATION
Vaccination is the administration of antigenic material (a vaccine) to stimulate an individual’s immune system to develop adaptive immunity to a pathogen. Vaccines can prevent or ameliorate morbidity from infection. The effectiveness of vaccination has been widely studied and verified; for example, the influenza vaccine, the HPV vaccine, and the chicken pox vaccine. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world.
CONDOMS
A condom is a barrier device commonly used during sexual intercourse to reduce the probability of pregnancy and spreading sexually transmitted diseases. It is put on a man’s erect penis and physically blocks ejaculated semen from entering the body of a sexual partner. Condoms are also used for collection of semen for use in infertility treatment. In the modern age, condoms are most often made from latex, but some are made from other materials such as polyurethane, polyisoprene, or lamb intestine. A female condom is also available, often made of nitrile. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.05%3A_Epidemiology_and_Public_Health/10.5D%3A__Public_Health_Measures_for_Disease_Control.txt |
Global health is the health of populations in a global context and transcends the perspectives and concerns of individual nations.
Learning Objectives
• Outline the various perspectives that provide the framework for global health initiatives: epidemiological, medical, economic and political approaches
Key Points
• Health problems that transcend national borders or have a global political and economic impact are often emphasized.
• The major international agency for health is the World Health Organization (WHO). Other important agencies with impact on global health activities include UNICEF, World Food Programme (WFP), United Nations University – International Institute for Global Health, and the World Bank.
• Global health is a research field at the intersection of medical and social science disciplines, such as demography, economics, epidemiology, political economy and sociology.
Key Terms
• health: The state of being free from physical or psychological disease, illness, or malfunction; wellness.
• populations: A population is all the organisms that both belong to the same group or species and live in the same geographical area.
• nations: A nation may refer to a community of people who share a common language, culture, ethnicity, descent, or history. In this definition, a nation has no physical borders.
Global Health
Global health is the health of populations in a global context and transcends the perspectives and concerns of individual nations. Health problems that transcend national borders or have a global political and economic impact are often emphasized. It has been defined as “the area of study, research and practice that places a priority on improving health and achieving equity in health for all people worldwide. ” Thus, global health is about worldwide improvement of health, reduction of disparities, and protection against global threats that disregard national borders. The application of these principles to the domain of mental health is called global mental health.
The major international agency for health is the World Health Organization (WHO). Other important agencies with impact on global health activities include UNICEF, World Food Programme (WFP), United Nations University – International Institute for Global Health, and the World Bank. A major initiative for improved global health is the United Nations Millennium Declaration and the globally endorsed Millennium Development Goals.
Global health is a research field at the intersection of medical and social science disciplines, such as demography, economics, epidemiology, political economy, and sociology. Through these different disciplinary perspectives, it focuses on determinants and the distribution of health in international contexts.
Global Health Perspectives
An epidemiological perspective identifies major global health problems. A medical perspective describes the pathology of major diseases, and promotes prevention, diagnosis, and treatment of these diseases.
An economic perspective emphasizes the cost-effectiveness and cost-benefit approaches for both individual and population health allocation. Aggregate analysis focuses on analysis for the health sector. For instance, governments and non-governmental organizations (NGOs) may engage in aggregate analysis.
Cost-effectiveness analysis compares the costs and health effects of an intervention to assess whether health investments are worthwhile from an economic perspective. It is necessary to distinguish between independent interventions and mutually exclusive interventions. For independent interventions, average cost-effectiveness ratios suffice. However, when mutually exclusive interventions are compared, it is essential to use incremental cost-effectiveness ratios. The latter comparisons suggest how to achieve maximal health care effects with the available resources.
Another ethical approach emphasizes distributional considerations. The Rule of Rescue, coined by A.R. Jonsen (1986), is one way to address distributional issues. This rule specifies that it is “a perceived duty to save endangered life where possible. ” John Rawls ideas on impartial justice is a contractual perspective on distribution. These ideas have been applied by Amartya Sen to address key aspects of health equity. Bioethics research also examines international obligations of justice, in three broadly clustered areas: When are international inequalities in health unjust? Where do international health inequalities come from? How do we meet health needs justly if we can’t meet them all?
A political approach emphasizes political economy considerations applied to global health. Political economy originally was the term for studying production, buying and selling, and their relations with law, custom, and government. Originating in moral philosophy (e.g., Adam Smith was professor of Moral Philosophy at the University of Glasgow), political economy of health is the study of how economies of states influence aggregate population health outcomes.
There are many perspectives and approaches to take when it comes to issues of global health, hence why the global health system is still struggling. Some perceive the immunization and prevention of disease to be a form of public democracy, others view it as a moral duty or an investment in self-protection. The journalist, Laurie Garrett explores the various perspectives shaping global health and suggests that it is due to perspective divergence that is hindering monetary funding and philanthropic efforts of organizations to properly control disease.
There are dangers to having divergent perspectives especially if it is a biased one; such as exemplified by Andrew Natsios of USAID, when he proclaimed that antiretrovirals should not be distributed to HIV-stricken Africa due to the occupants lacking a concept of time and clocks to properly facilitate the proper sequence of drug consumption. In addition, divergent perspectives can lead to “stove-piping”, which localizes funding to only specific causes while neglecting the larger and more important issues. The most important aspect in achieving global health is to take on a research approach and act accordingly to data and proven research because global health needs to be focused on as a whole, rather than specific causes. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.05%3A_Epidemiology_and_Public_Health/10.5E%3A_Global_Health.txt |
An emerging infectious disease is a disease with a rate of incidence that has increased in the past 20 years, and could increase in the near future.
Learning Objectives
• Give examples of emerging and remerging infectious diseases
Key Points
• Emerging infections account for at least 12% of all human pathogens.
• Emerging infections deseases are caused by newly identified species or strains that may have evolved from a known infection or spread to a new population or area undergoing ecologic transformation, or be reemerging infections, such as drug resistant tuberculosis.
• Adverse synergistic interactions between emerging diseases and other infectious and non-infectious conditions leading to the development of novel syndemics are of growing concern.
Key Terms
• emerging infectious disease: An emerging infectious disease (EID) is an infectious disease with an incidence rate that has increased in the past 20 years and could increase in the near future. Emerging infections account for at least 12% of all human pathogens.
• pathogens: A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host. The host may be an animal (including humans), a plant, or even another microorganism.
• species: In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring.
An emerging infectious disease (EID) is an infectious disease whose incidence has increased in the past 20 years, and could increase in the near future. Emerging infections account for at least 12% of all human pathogens. EIDs are caused by newly identified species or strains (e.g., SARS, AIDS) that may have evolved from a known infection (e.g., influenza), or spread to a new population (e.g., West Nile virus ), or to an area undergoing ecologic transformation (e.g., Lyme disease). They could also be reemerging infections, such as drug resistant tuberculosis. Of growing concern are adverse synergistic interactions between emerging diseases and other infectious and non-infectious conditions leading to the development of novel syndemics.
SARS
Severe acute respiratory syndrome (SARS) is a viral respiratory disease in humans which is caused by the SARS coronavirus (SARS-CoV). Between November 2002 and July 2003, an outbreak of SARS in Hong Kong nearly became a pandemic, with 8,422 cases and 916 deaths worldwide (10.9% fatality), according to the World Health Organization (WHO). Within weeks, SARS spread from Hong Kong to infect individuals in 37 countries. The last infected human case of the outbreak occurred in June 2003, and there was a laboratory-induced infection case in 2004. SARS is not claimed to have been eradicated (unlike smallpox), as it may still be present in its natural host reservoirs (animal populations) and may return to the human population. During the outbreak, the fatality of SARS was less than 1% for people aged 24 or younger, 6% for those 25 to 44, 15% for those 45 to 64, and more than 50% for those over 65. For comparison, the fatality of influenza is usually under 0.03% (primarily among the elderly), but rose to 2% during the most severe pandemic to date.
HIV
Human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). During the initial infection a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses it interferes more and more with the immune system, making people much more likely to get infections, including opportunistic infections, and tumors that do not usually affect people with working immune systems.
Influenza
Influenza, commonly known as the flu, is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae, the influenza viruses. The most common symptoms are chills, fever, sore throat, muscle pains, headache (often severe), coughing, weakness/fatigue and general discomfort. Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a more severe disease caused by a different type of virus. Influenza may produce nausea and vomiting, particularly in children, but these symptoms are more common in the unrelated gastroenteritis, which is sometimes inaccurately referred to as “stomach flu” or “24-hour flu. ”
West Nile Virus
West Nile virus (WNV) is a mosquito-borne zoonotic arbovirus belonging to the genus flavivirus in the family flaviviridae. This flavivirus is found in temperate and tropical regions of the world. It was first identified in the West Nile subregion in the East African nation of Uganda in 1937. Prior to the mid 1990s, WNV disease occurred only sporadically and was considered a minor risk for humans. However, there was an outbreak in Algeria in 1994, with cases of WNV-caused encephalitis, and the first large outbreak in Romania in 1996, with a high number of cases with neuroinvasive disease. WNV has now spread globally, with the first case in the Western Hemisphere being identified in New York City in 1999; over the next 5 years, the virus spread across the continental United States, north into Canada, and southward into the Caribbean Islands and Latin America. WNV also spread to Europe, beyond the Mediterranean Basin. A new strain of the virus was recently (2012) identified in Italy. WNV is now considered to be an endemic pathogen in Africa, Asia, Australia, the Middle East, Europe and in the United States, which in 2012 has experienced one of its worst epidemics.
Tuberculosis
Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body. It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit their saliva through the air. Most infections are asymptomatic and latent, but about one in ten latent infections eventually progresses to active disease which, if left untreated, kills more than 50% of those so infected. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.05%3A_Epidemiology_and_Public_Health/10.5F%3A__Emerging_and_Reemerging_Infectious_Diseases.txt |
Biological warfare (BW) is the use of biological toxins or infectious agents with the intent to kill or incapacitate.
Learning Objectives
• Recognize the characteristics of biological weapons
Key Points
• Biological weapons (often termed “bio-weapons”, “biological threat agents”, or “bio-agents”) are living organisms or replicating entities (viruses) that reproduce or replicate within their host victims.
• Biological weapons may be employed in various ways to gain a strategic or tactical advantage over an adversary, either by threats or by actual deployments.
• As a tactical weapon for military use, a significant problem with a BW attack is that it would take days to be effective, and therefore might not immediately stop an opposing force.
Key Terms
• Biological warfare: Biological warfare (BW) — also known as germ warfare — is the use of biological toxins or infectious agents such as bacteria, viruses, and fungi with the intent to kill or incapacitate humans, animals, or plants as an act of war.
• psychochemical weapon: Agents used within the context of military aggression.
Biological warfare (BW) — also known as germ warfare — is the use of biological toxins or infectious agents such as bacteria, viruses, and fungi with the intent to kill or incapacitate humans, animals, or plants as an act of war. Biological weapons (often termed “bio-weapons”, “biological threat agents”, or “bio-agents”) are living organisms or replicating entities (viruses) that reproduce or replicate within their host victims. Entomological (insect) warfare is also considered a type of BW.
Biological weapons may be employed in various ways to gain a strategic or tactical advantage over an adversary, either by threats or by actual deployments. Like some chemical weapons, biological weapons may also be useful as area denial weapons. These agents may be lethal or non-lethal, and may be targeted against a single individual, a group of people, or even an entire population. They may be developed, acquired, stockpiled, or deployed by nation states or by non-national groups. In the latter case, or if a nation-state uses it clandestinely, it may also be considered bioterrorism.
There is an overlap between BW and chemical warfare, as the use of toxins produced by living organisms is considered under the provisions of both the Biological Weapons Convention and the Chemical Weapons Convention. Toxins and psychochemical weapons are often referred to as midspectrum agents. Unlike bioweapons, these midspectrum agents do not reproduce in their host and are typically characterized by shorter incubation periods.
Offensive biological warfare, including the mass production, stockpiling, and use of biological weapons, was outlawed by the 1972 Biological Weapons Convention (BWC). The rationale behind this treaty, which has been ratified or acceded to by 165 countries as of 2011, is to prevent a biological attack which could conceivably result in large numbers of civilian fatalities and cause severe disruption to economic and societal infrastructure. Many countries, including signatories of the BWC, currently pursue research into the defense or protection against BW, which is not prohibited by the BWC.
A nation or group that can pose a credible threat of mass casualty has the ability to alter the terms on which other nations or groups interact with it. Biological weapons allow for the potential to create a level of destruction and loss of life far in excess of nuclear, chemical, or conventional weapons, relative to their mass and cost of development and storage. Therefore, biological agents may be useful as strategic deterrents in addition to their utility as offensive weapons on the battlefield.
As a tactical weapon for military use, a significant problem with a BW attack is that it would take days to be effective, and therefore might not immediately stop an opposing force. Some biological agents (especially smallpox, plague, and tularemia) have the capability of person-to-person transmission via aerosolized respiratory droplets. This feature can be undesirable, as the agent or agents may be transmitted by this mechanism to unintended populations, including neutral or even friendly forces. While containment of BW is less of a concern for certain criminal or terrorist organizations, it remains a significant concern for the military and civilian populations of virtually all nations. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.05%3A_Epidemiology_and_Public_Health/10.5G%3A_Biological_Weapons.txt |
Technology aids in the identification of new infectious agents, but it also contributes to the emergence of new diseases.
Learning Objectives
• Give examples demonstrating the positive and negative impacts technology has had on new infectious agents
Key Points
• Advanced technology enables rapid identification of pathogens causing disease outbreaks and helps accelerate treatment strategies.
• The effect of new technology on the environment is related to the emergence of many new infectious diseases.
• Infectious diseases are sometimes called ” contagious ” when they are easily transmitted by contact with an ill person or their secretions (e.g., influenza).
Key Terms
• infectious: Infectious diseases, also known as transmissible diseases or communicable diseases, comprise clinically evident illness (i.e., characteristic medical signs and/or symptoms of disease) resulting from the infection, presence, and growth of pathogenic biological agents in an individual host organism.
• pathogens: A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host. The host may be an animal (including humans), a plant, or even another microorganism.
Technology: The Good
The use of advanced technology and molecular methods for detection, identification, and characterization of infectious agents is gaining importance in clinical microbiology laboratories. Emerging and re-emerging pathogens pose several challenges to diagnosis, treatment, and public health surveillance. Identification of an emerging pathogen by conventional methods is difficult and time-consuming due to the ‘novel’ nature of the agent. Identification requires a large array of techniques including cell cultures, inoculation of animals, cultivation using artificial media, histopathological evaluation of tissues (if available), and serological techniques using surrogate antigens.
Looking back at past epidemics or outbreaks caused by previously unknown infectious agents, we realize that identification and characterization of a new infectious agent can take years, decades, or even centuries. Such time frames have been decreased to weeks or months by the use of powerful molecular techniques, as seen with the identification of severe acute respiratory syndrome coronavirus (SARS-CoV) within weeks of the first cases reported, the discovery of a new hantavirus in North America in 1993, and the detection of bacteria as etiological pathogens of human infections such as Ehrlichia chaffeensis and Anaplasma phagocytophilum in human monocytotropic ehrlichiosis and human granulocytotropic anaplasmosis, respectively.
Molecular techniques offer several advantages over conventional methods, including high sensitivity and specificity, speed, ease of standardization, and automation. Other advantages include identification of novel, non-cultivable or very slowly growing organisms, strain typing in epidemiological studies, antimicrobial susceptibility determination, and monitoring treatment by measuring bacterial or viral loads.
Technology: The Bad
The effects of new technology on the environment are related to the emergence of many infectious diseases. For example, Lyme disease, hantavirus pulmonary syndrome (HPS), and Lassa fever all emerged when humans began encountering the insect vector (for Lyme disease) or rodent host (for HPS and Lassa fever) of the causative agents in greater numbers than ever before. Factors related to the emergence of infectious diseases such as Legionnaire disease and hemolytic uremic syndrome include changing technologies: air conditioning systems and mass food production, respectively.
Technology: The Ugly
Several human activities have led to the emergence and spread of new diseases:
ENCROACHMENT ON WILDLIFE HABITATS
The construction of new villages and housing developments in rural areas forces animals to live in dense populations, creating opportunities for microbes to mutate and emerge.
CHANGES IN AGRICULTURE
The introduction of new crops attracts new crop pests and the microbes they carry to farming communities, exposing people to unfamiliar diseases.
DESTRUCTION OF RAIN FORESTS
As countries make use of their rain forests by building roads and clearing areas for settlement or commercial ventures, people encounter insects and other animals harboring previously unknown microorganisms.
UNCONTROLLED URBANIZATION
The rapid growth of cities in many developing countries tends to concentrate large numbers of people into crowded areas with poor sanitation. These conditions foster transmission of contagious diseases.
MODERN TRANSPORT
Ships and other cargo carriers often harbor unintended ‘passengers’ that can spread diseases to faraway destinations. With international air travel, people infected with a disease can carry it to distant lands, or home to their families, before their first symptoms appear. | textbooks/bio/Microbiology/Microbiology_(Boundless)/10%3A_Epidemiology/10.05%3A_Epidemiology_and_Public_Health/10.5H%3A_Technology_and_New_Infectious_Agents.txt |
An epidemic occurs when new cases of a disease, in a given human population, and during a given period, substantially exceed expectations.
Learning Objectives
• Give examples of current epidemics
Key Points
• Epidemiologists often consider the term outbreak to be synonymous to epidemic, but the general public typically perceives outbreaks to be more local and less serious than epidemics.
• Epidemics of infectious disease are generally caused by a change in the ecology of the host population (e.g. increased stress or increase in the density of a vector species ), a genetic change in the parasite population or the introduction of a new parasite to a host population.
• In the 20th century three influenza pandemics occurred, each caused by the appearance of a new strain of the virus in humans, and killed tens of millions of people.
Key Terms
• epidemic: A widespread disease that affects many individuals in a population.
• population: A collection of organisms of a particular species, sharing a particular characteristic of interest, most often that of living in a given area.
• infectious: Infectious diseases, also known as transmissible diseases or communicable diseases, comprise clinically evident illness (i.e., characteristic medical signs and/or symptoms of disease) resulting from the infection, presence, and growth of pathogenic biological agents in an individual host organism.
Epidemics
In epidemiology, an epidemic occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience. Epidemiologists often consider the term outbreak to be synonymous to epidemic, but the general public typically perceives outbreaks to be more local and less serious than epidemics.
CAUSES
Epidemics of infectious disease are generally caused by a change in the ecology of the host population (e.g. increased stress or increase in the density of a vector species), a genetic change in the parasite population or the introduction of a new parasite to a host population (by movement of parasites or hosts). Generally, an epidemic occurs when host immunity to a parasite population is suddenly reduced below that found in the endemic equilibrium and the transmission threshold is exceeded.
EPIDEMIC VS. PANDEMIC
An epidemic may be restricted to one location; however, if it spreads to other countries or continents and affects a substantial number of people, it may be termed a pandemic. The declaration of an epidemic usually requires a good understanding of a baseline rate of incidence; epidemics for certain diseases, such as influenza, are defined as reaching some defined increase in incidence above this baseline. A few cases of a very rare disease may be classified as an epidemic, while many cases of a common disease (such as the common cold) would not.
INFLUENZA EPIDEMICS
Influenza is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae, the influenza viruses. The most common symptoms are chills, fever, sore throat, muscle pains, headache (often severe), coughing, weakness/fatigue and general discomfort. Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a more severe disease caused by a different type of virus. Influenza may produce nausea and vomiting, particularly in children, but these symptoms are more common in the unrelated gastroenteritis, which is sometimes inaccurately referred to as “stomach flu” or “24-hour flu”.
Typically, influenza is transmitted through the air by coughs or sneezes, creating aerosols containing the virus. Influenza can also be transmitted by direct contact with bird droppings or nasal secretions, or through contact with contaminated surfaces. Airborne aerosols have been thought to cause most infections, although which means of transmission is most important is not absolutely clear. Influenza viruses can be inactivated by sunlight, disinfectants and detergents. As the virus can be inactivated by soap, frequent hand washing reduces the risk of infection.
Influenza spreads around the world in seasonal epidemics, resulting in about three to five million yearly cases of severe illness and about 250,000 to 500,000 yearly deaths, rising to millions in some pandemic years.
In the 20th century three influenza pandemics occurred, each caused by the appearance of a new strain of the virus in humans, and killed tens of millions of people. Often, new influenza strains appear when an existing flu virus spreads to humans from another animal species, or when an existing human strain picks up new genes from a virus that usually infects birds or pigs. An avian strain named H5N1 raised the concern of a new influenza pandemic after it emerged in Asia in the 1990s, but it has not evolved to a form that spreads easily between people.
In April 2009 a novel flu strain evolved that combined genes from human, pig, and bird flu. Initially dubbed “swine flu” and also known as influenza A/H1N1, it emerged in Mexico, the United States, and several other nations. The World Health Organization officially declared the outbreak to be a pandemic level 6 on 11 June 2009. However, the WHO’s declaration of a pandemic level 6 was an indication of spread, not severity; the strain actually having a lower mortality rate than common flu outbreaks.
VACCINATIONS
Vaccinations against influenza are usually made available to people in developed countries. Farmed poultry is often vaccinated to avoid decimation of the flocks. The most common human vaccine is the trivalent influenza vaccine (TIV) that contains purified and inactivated antigens against three viral strains. Typically, this vaccine includes material from two influenza A virus subtypes and one influenza B virus strain. The TIV carries no risk of transmitting the disease, and it has very low reactivity. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus evolves rapidly, and new strains quickly replace the older ones.
Antiviral drugs such as the neuraminidase inhibitor oseltamivir (Tamiflu) have been used to treat influenza; however, their effectiveness is difficult to determine due to much of the data remaining unpublished.
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Immunology is a branch of biology that covers the study of immune systems in all organisms. Immunology charts, measures, and contextualizes the: physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders (such as autoimmune diseases, hypersensitivities, immune deficiency, and transplant rejection); the physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ, and in vivo.
Thumbnail: Scanning electron micrograph of a phagocyte (yellow, right) phagocytosing anthrax bacilli (orange, left). (CC BY 2.5; Volker Brinkmann via PLOS).
11: Immunology
The immune system includes primary lymphoid organs, secondary lymphatic tissues and various cells in the innate and adaptive immune systems.
Learning Objectives
• Recognize the cells and organs of the immune system and their functions
Key Points
• The key primary lymphoid organs of the immune system are the thymus and bone marrow, and secondary lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and skin and liver.
• Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system.
• The innate leukocytes include the phagocytes ( macrophages, neutrophils, and dendritic cells ), mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens and are also important mediators in the activation of the adaptive immune system.
• The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow.
• The lymphatic system is a part of the circulatory system, comprising a network of conduits called lymphatic vessels. The lymphatic system has multiple functions such as the transportation of white blood cells to and from the lymph nodes into the bones.
Key Terms
• lymphocytes: A lymphocyte is a type of white blood cell in the vertebrate immune system. The three major types of lymphocyte are T cells, B cells and natural killer (NK) cells. T cells (thymus cells) and B cells (bursa-derived cells) are the major cellular components of the adaptive immune response.
• Leukocytes: Cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist.
Immune System Organs
The key primary lymphoid organs of the immune system include the thymus and bone marrow, as well as secondary lymphatic tissues including spleen, tonsils, lymph vessels, lymph nodes, adenoids, skin, and liver.
The thymus “educates” T cells and provides an inductive environment for the development of T cells from hematopoietic progenitor cells. The thymus is largest and most active during the neonatal and pre-adolescent periods of development. By the early teens, the thymus begins to atrophy and thymic stroma is replaced by adipose tissue. Nevertheless, residual T-lymphopoiesis continues throughout adult life.
Bone marrow is the flexible tissue found in the interior of bones. In humans, red blood cells are produced in the heads of long bones. The red bone marrow is a key element of the lymphatic system, being one of the primary lymphoid organs that generate lymphocytes from immature hematopoietic progenitor cells. Bone marrow and thymus constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes.
The lymphatic system is a part of the circulatory system, comprising a network of conduits called lymphatic vessels that carry a clear fluid, called lymph, unidirectionally towards the heart. The lymphatic system has multiple interrelated functions including the transportation of white blood cells to and from the lymph nodes into the bones, and the transportation of antigen -presenting cells (such as dendritic cells) to the lymph nodes where an immune response is stimulated. Lymphoid tissue is found in many organs, particularly the lymph nodes.
The spleen is similar in structure to a large lymph node and acts primarily as a blood filter. It synthesizes antibodies in its white pulp and removes antibody-coated bacteria along with antibody-coated blood cells by way of blood and lymph node circulation.
The palatine tonsils and the nasopharyngeal tonsil are lymphoepithelial tissues located near the oropharynx and nasopharynx. These immunocompetent tissues are the immune system’s first line of defense against ingested or inhaled foreign pathogens. The fundamental immunological roles of tonsils aren’t yet understood.
Lymph nodes are distributed widely throughout areas of the body, including the armpit and stomach, and linked by lymphatic vessels. Lymph nodes are garrisons of B, T and other immune cells. Lymph nodes act as filters or traps for foreign particles and are important in the proper functioning of the immune system. They are packed tightly with the white blood cells, called lymphocytes and macrophages.
The skin is one of the most important parts of the body because it interfaces with the environment, and is the first line of defense from external factors, acting as an anatomical barrier from pathogens and damage between the internal and external environment in bodily defense. Langerhans cells in the skin are part of the adaptive immune system.
The liver has a wide range of functions, including immunological effects—the reticuloendothelial system of the liver contains many immunologically active cells, acting as a “sieve” for antigens carried to it via the portal system.
Immune System Cells
Leukocytes (white blood cells) are immune system cells involved in defending the body against infectious disease and foreign materials. Five different types of leukocytes exist, all produced and derived from a multipotent cell in the bone marrow known as a hematopoietic stem cell. The innate leukocytes include the phagocytes, mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens and are important mediators in the activation of the adaptive immune system.
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte. During the acute phase of inflammation neutrophils migrate toward the site of inflammation and are usually the first cells to arrive at the scene of infection. Macrophages reside within tissues and produce a wide array of chemicals. They also act as scavengers, ridding the body of worn-out cells and other debris, and as antigen-presenting cells that activate the adaptive immune system. Dendritic cells are phagocytes in tissues that are in contact with the external environment, and are located mainly in the skin, nose, lungs, stomach, and intestines. These cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigen to T-cells, one of the key cell types of the adaptive immune system.
Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis.
Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites, and play a role in allergic reactions, such as asthma.
Natural killer cells are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses.
The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow.
T cells recognize a “non-self” target, such as a pathogen, only after antigens have been processed and presented in combination with a “self” receptor, called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell, which kills cells that are infected with viruses (and other pathogens) or are otherwise damaged or dysfunctional, and the helper T cell, which regulates both innate and adaptive immune responses and helps determine which immune responses the body makes to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. A third, minor subtype are the γ T cells that recognize intact antigens not bound to MHC receptors.
In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, which recognizes whole pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.01%3A_Overview_of_Immunity/11.1A%3A_Cells_and_Organs_of_the_Immune_System.txt |
Learning Objectives
• Outline the relationships between humans and microbes: non-pathogenic and pathogenic
The Human Microbiome Project
The Human Microbiome Project (HMP) is a United States National Institutes of Health initiative aimed at identifying and characterizing the microorganisms which are found in association with both healthy and diseased humans.
Total microbial cells found in association with humans may exceed the total number of cells making up the human body by a factor of ten-to-one. The total number of genes associated with the human microbiome could exceed the total number of human genes by a factor of 100-to-one.
Organisms expected to be found in the human microbiome may generally be categorized as bacteria (the majority), archaea, yeasts, and single-celled eukaryotes as well as various helminth parasites and viruses, such as those that infect cellular microbiome organisms.
The HMP project discovered several “surprises”, including:
• Bacterial protein -coding genes are estimated as 360 times more abundant than human genes.
• Microbial metabolic activities, for example, digestion of fats, are not always provided by the same bacterial species.
• Components of the human microbiome change over time, affected by a patient disease state and medication.
Examples of Non-pathogenic Interactions
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. The human body, consisting of about 10 trillion cells, carries about ten times as many microorganisms in the intestines. The metabolic activities performed by these bacteria resemble those of an organ, leading some to liken gut bacteria to a “forgotten” organ.
Bacteria make up most of the flora in the colon and up to 60% of the dry mass of feces. Between 300 and 1000 different species live in the gut. It is probable that 99% of the bacteria come from about 30 or 40 species. Fungi and protozoa also make up a part of the gut flora, but little is known about their activities.
The relationship between gut flora and humans is thought to be not merely commensal, but rather a mutualistic relationship. Though people can survive without gut flora, the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system, preventing growth of harmful, pathogenic bacteria, regulating the development of the gut, producing vitamins for the host, and producing hormones to direct the host to store fats. In certain conditions, some species can cause disease by producing infection or increasing the host’s cancer risk.
The skin microbiota are composed mostly of bacteria of which there are around 1000 species upon human skin from 19 phyla. The total number of bacteria on an average human has been estimated at 1012.
Skin flora are usually non-pathogenic and either commensal or mutualistic. The benefits of bacteria include preventing transient pathogenic organisms from colonizing the skin surface, either by competing for nutrients, secreting chemicals against them, or stimulating the skin’s immune system. Resident microbes can cause skin diseases and enter the blood system creating life-threatening diseases particularly in immunosuppressed people.
Pathogenic Interactions
Among the almost infinite varieties of microorganisms, relatively few cause disease in otherwise healthy individuals. Infectious disease results from the interplay between those few pathogens and the defenses of the hosts they infect. Infectious diseases comprise clinically evident illness resulting from the infection, and the presence and growth of pathogenic biological agents in an individual host organism. Infectious pathogens include some viruses, bacteria, fungi, protozoa, multicellular parasites, and aberrant proteins known as prions. Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host. Their intrinsic virulence is due to their need to reproduce and spread.
Organisms which cause an infectious disease in a host with depressed resistance are classified as opportunistic pathogens. Opportunistic disease may be caused by microbes that are ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal tract. They may also result from (otherwise innocuous) microbes acquired from other hosts or from the environment as a result of traumatic introduction (as in surgical wound infections). An opportunistic disease requires impairment of host defenses, which may occur as a result of genetic defects, exposure to antimicrobial drugs or immunosuppressive chemicals, exposure to ionizing radiation, or as a result of an infectious disease with immunosuppressive activity.
The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading the immune system. Bacteria often overcome physical barriers by secreting enzymes that digest the barrier. An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host. The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is antigenic variation: rapid changes of non-essential epitopes on the surface of the pathogen, while keeping essential epitopes concealed.
Key Points
• Though people can survive without gut flora, the microorganisms perform a host of useful functions: fermenting unused energy substrates, training the immune system, preventing growth of harmful bacteria, regulating the development of the gut, and producing vitamins and hormones for the host.
• Organisms expected to be found in the human microbiome may generally be categorized as bacteria (the majority), archaea, yeasts, and single-celled eukaryotes as well as various helminth parasites and viruses.
• Skin flora are usually either commensal or mutualistic. The benefits of bacteria include preventing transient pathogenic organisms from colonizing the skin surface. Resident microbes can cause skin diseases and create life-threatening illness particularly in immunosuppressed people.
• Among the almost infinite varieties of microorganisms, relatively few cause disease in otherwise healthy individuals. Infectious disease results from the interplay between those few pathogens and the defenses of the hosts they infect.
• Primary pathogens cause disease as a result of their activity in the healthy host and their intrinsic virulence is due to their need to reproduce and spread. Organisms that cause an infectious disease in a host with depressed resistance are classified as opportunistic.
• The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading the immune system.
Key Terms
• Human microbiome: The aggregate of microorganisms that reside on the surface and in deep layers of skin, in the saliva and oral mucosa, in the conjunctiva, and in the gastrointestinal tracts. They include bacteria, fungi, and archaea. Some of these organisms perform tasks that are useful for the human host. However, the majority have no known beneficial or harmful effect.
• Primary pathogen: These pathogens cause disease as a result of their presence or activity within the normal, healthy host. Their intrinsic virulence (the severity of the disease they cause) is due to their need to reproduce and spread.
• Opportunistic pathogen: Organisms which cause an infectious disease in a host with depressed resistance are classified as opportunistic pathogens. Opportunistic disease may be caused by microbes that are ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract. They may also result from (otherwise innocuous) microbes acquired from other hosts or from the environment as a result of traumatic introduction. An opportunistic disease requires impairment of host defenses. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.01%3A_Overview_of_Immunity/11.1B%3A__Overview_of_Human-Microbial_Reactions.txt |
The immune system is a system of biological structures and processes within an organism that protects against disease.
Learning Objectives
• Distinguish between innate and adaptive immunity
Key Points
• Pathogens can rapidly evolve and adapt to avoid detection and neutralization by the immune system. As a result, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. The immune system protects from infection with layered defenses of increasing specificity.
• Physical barriers prevent pathogens from entering the organism. If these barriers are breached, the innate immune system provides an immediate, non-specific response. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system.
• Immunity is a biological term that describes a state of having sufficient biological defences to avoid infection, disease, or other unwanted biological invasion.
• Innate, or nonspecific, immunity is the natural resistance with which a person is born. It provides resistance through several physical, chemical, and cellular approaches.
• Adaptive immunity is often sub-divided into two major types acording to how the immunity was introduced. Naturally acquired immunity occurs through non-deliberate contact with a disease causing agent, whereas artificially acquired immunity develops through deliberate actions such as vaccination.
• Immunology is a branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and disease.
Key Terms
• Adaptive (acquired) immunity: The creation of immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.
• Innate immunity: The natural resistance with which a person is born. It provides resistance through several physical, chemical, and cellular approaches.
• Self molecules: Those components of an organism’s body that can be distinguished by the immune system from foreign substances.
The immune system is a system of biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, from viruses to parasitic worms, and distinguish them from the organism’s own healthy tissue.
Pathogens can rapidly evolve and adapt to avoid detection and neutralization by the immune system. As a result, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. Even simple unicellular organisms, such as bacteria, possess a rudimentary immune system in the form of enzymes that protect against bacteriophage infections. Other basic immune mechanisms including include phagocytosis, antimicrobial peptides called defensins, and the complement system, which evolved in ancient eukaryotes and remain in modern descendants, such as plants and insects. Jawed vertebrates have even more sophisticated defense mechanisms, including the ability to adapt over time to recognize specific pathogens more efficiently. Adaptive (acquired) immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.
Innate and Adaptive Immunity
The immune system protects organisms from infection with layered defenses of increasing specificity. Physical barriers prevent pathogens, such as bacteria and viruses, from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. The immune system adapts its response during an infection in order to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks when this pathogen is encountered. Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non- self molecules, where self molecules are those components of an organism’s body that can be distinguished from foreign substances by the immune system.
Immunity is a biological term that describes a state of having sufficient biological defences to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components.
INNATE IMMUNITY
Innate, or nonspecific, immunity is the natural resistance with which a person is born. It provides resistance through several physical, chemical, and cellular approaches. Microbes first encounter the epithelial layers (physical barriers that line our skin and mucous membranes). Subsequent general defenses include secreted chemical signals (cytokines), antimicrobial substances, fever, and phagocytic activity associated with the inflammatory response. The phagocytes express cell surface receptors that can bind and respond to common molecular patterns expressed on the surface of invading microbes. Through these approaches, innate immunity can prevent the colonization, entry, and spread of microbes.
ADAPTIVE IMMUNITY
Adaptive immunity is often sub-divided into two major types depending on how the immunity was introduced. Naturally acquired immunity occurs through contact with a disease causing agent, when the contact was not deliberate, whereas artificially acquired immunity develops only through deliberate actions such as vaccination. Both naturally and artificially acquired immunity can be further subdivided depending on whether immunity is induced in the host or passively transferred from an immune host. Passive immunity is acquired through transfer of antibodies or activated T cells from an immune host, and is short lived—usually lasting only a few months. Active immunity is induced in the host itself by antigen, and lasts much longer, sometimes the entire lifetime.
A further subdivision of adaptive immunity is characterized by the cells involved; humoral immunity is the aspect of immunity that is mediated by secreted antibodies, whereas the protection provided by cell-mediated immunity involves T lymphocytes alone. Humoral immunity is active when the organism generates its own antibodies, and passive when antibodies are transferred between individuals. Similarly, cell-mediated immunity is active when the organism’s own T cells are stimulated and passive when T cells come from another organism.
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LEARNING OBJECTIVe
• Describe the role of natural killer cells in the immune response
Lymphocytes are leukocytes (white blood cells) that are histologically identifiable by their large, darkly-staining nuclei; they are small cells with very little cytoplasm. After a pathogen enters the body, infected cells are identified and destroyed by natural killer (NK) cells, which are a type of lymphocyte that can kill cells infected with viruses or tumor cells (abnormal cells that uncontrollably divide and invade other tissue). While NK cells are part of the innate immune response, they are best understood relative to their counterparts in the adaptive immune response,T cells, which are also classified as lymphocytes.
T cells are lymphocytes that mature in the thymus gland and identify intracellular infections, especially from viruses, by the altered expression of major histocompatibility class (MHC) I molecules on the surface of infected cells. MHC I molecules are proteins on the surfaces of all nucleated cells which help the immune system distinguish between “self” and “non-self.” If the cell is infected, the MHC I molecules display fragments of proteins from the infectious agents to T-cells. Healthy cells do not display any proteins and will be ignored by the immune system, while the cells identified as “non-self” by foreign proteins will be attacked by the immune system.
An infected cell (or a tumor cell) is often incapable of synthesizing and displaying MHC I molecules appropriately. The metabolic resources of cells infected by some viruses produce proteins that interfere with MHC I processing and/or trafficking to the cell surface. The reduced MHC I on host cells varies from virus to virus and results from active inhibitors being produced by the viruses. This process can deplete host MHC I molecules on the cell surface, which prevents T-cells from recognizing them, but which NK cells detect as “unhealthy” or “abnormal” while searching for cellular MHC I molecules. As such, NK cells offer a complementary check for unhealthy cells, relative to T cells. Similarly, the dramatically-altered gene expression of tumor cells leads to expression of extremely- deformed or absent MHC I molecules that also signal “unhealthy” or “abnormal.”
NK cells are always active; an interaction with normal, intact MHC I molecules on a healthy cell disables the killing sequence, causing the NK cell to move on. After the NK cell detects an infected or tumor cell, its cytoplasm secretes granules comprised of perforin: a destructive protein that creates a pore in the target cell. Granzymes are released along with the perforin in the immunological synapse. A granzyme, a protease that digests cellular proteins, induces the target cell to undergo programmed cell death, or apoptosis. Phagocytic cells then digest the cell debris left behind. NK cells are constantly patrolling the body. They are an effective mechanism for controlling potential infections and preventing cancer progression.
Key Points
• Natural killer (NK) cells are lymphocytes (a subclass of white blood cells) that recognize infected or tumorogenic cells and kill them.
• Unlike the related T cells, NK cells do not recognize fragments of the infecting particle, but rather the incorrect display of major histocompatibility complex ( MHC ) I molecules.
• NK cells are always active, but will not perform their killing function on cells with intact MHC I molecules.
• When NK cells detect an infected or tumor cell, they secrete granules that contain perforin, creating a pore in the target cell; granzymes then pass through these pores, degrading cellular proteins, causing cells to undergo apoptosis.
Key Terms
• lymphocyte: a type of white blood cell or leukocyte that is divided into two principal groups and a null group: B-cells, T-cells, and natural killer (NK) cells
• major histocompatibility complex: a protein present on the extracellular surface of the cell that displays portions of the proteins that are degraded inside the cell
• T cell: a lymphocyte, from the thymus, that can recognize specific antigens and can activate or deactivate other immune cells | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.02%3A_The_Innate_Immune_Response/11.2A%3A_Natural_Killer_Cells.txt |
The innate immune response has physical and chemical barriers that exist as the first line of defense against infectious pathogens.
Learning Objectives
• Describe physical and chemical barriers in the innate immune response
Key Points
• The skin, or epithelial surface, serves as the primary barrier to microbial entry into the body; skin peeling, drying out, and the skin’s acidity all serve to dislodge or kill foreign pathogens.
• Orifices such as the eyes and mouth, which are not covered by skin, have other mechanisms by which they prevent entry; tears wash away microbes, while cilia in the nasal passages and respiratory tract push mucus (which traps pathogens) out of the body.
• Many chemical barriers also exist once pathogens make it past the outer physical barriers; the acidity of the stomach ensures that few organisms arriving with food survive the digestive system.
Key Terms
• cilium: a hairlike organelle projecting from a eukaryotic cell (such as unicellular organism or one cell of a multicelled organism), which serves either for locomotion by moving or as sensors
• microbicidal: functioning to reduce the infectivity of microbes
Physical and chemical barriers
The immune system comprises both innate and adaptive immune responses. Innate immunity occurs naturally due to genetic factors or physiology. It is not induced by infection or vaccination, but is constantly available to reduce the workload for the adaptive immune response. The adaptive immune response expands over time, storing information about past infections and mounting pathogen-specific defenses. Both the innate and adaptive levels of the immune response involve secreted proteins, receptor-mediated signaling, and intricate cell -to-cell communication. From an historical perspective, the innate immune system developed early in animal evolution, roughly a billion years ago, as an essential response to infection. In the innate immune response, any pathogenic threat triggers a consistent sequence of events that can identify the type of pathogen and either clear the infection independently or mobilize a highly-specialized adaptive immune response.
Before any immune factors are triggered, the skin (also known as the epithelial surface) functions as a continuous, impassable barrier to potentially-infectious pathogens. The skin is considered the first defense of the innate immune system; it is the first of the nonspecific barrier defenses. Pathogens are killed or inactivated on the skin by desiccation (drying out) and by the skin’s acidity. In addition, beneficial microorganisms that coexist on the skin compete with invading pathogens, preventing infection. Desquamation, or peeling skin, also serves to dislodge organisms that have adhered to the surface of the body and are awaiting entry. Regions of the body that are not protected by skin (such as the eyes and mucous membranes ) have alternative methods of defense. These include tears in the eyes; mucous membranes that provide partial protection despite having to allow absorption and secretion; mucus secretions that trap and rinse away pathogens; and cilia (singular cilium) in the nasal passages and respiratory tract that push the mucus with the pathogens out of the body. Furthermore, tears and mucus secretions contain microbicidal factors that prevent many infections from entering via these routes.
Despite these barriers, pathogens may enter the body through skin abrasions or punctures, or by collecting on mucosal surfaces in large numbers that overcome the mucus or cilia. Some pathogens have evolved specific mechanisms that allow them to overcome physical and chemical barriers.
Once inside, the body still has many other defenses, including chemical barriers. Some of these include the low pH of the stomach, which inhibits the growth of pathogens; blood proteins that bind and disrupt bacterial cell membranes; and the process of urination, which flushes pathogens from the urinary tract. The blood-brain barrier also protects the nervous system from pathogens that have already entered the blood stream, but would do significantly more damage if they entered the central nervous system.
11.2C: The Complement System
Around 20 soluble proteins comprise the complement system, which helps destroy extracellular microorganisms that have invaded the body.
Learning Objectives
• Explain how the complement system aids antibody response
Key Points
• The complement system is so named because it is complementary to the antibody response of the adaptive immune system.
• The complement system proteins are produced continuously by the liver and macrophages, are abundant in the blood serum, and are capable of immediate response to infecting microorganisms.
• The complement system works by first having several proteins bind to a target; this binding event then begins a series of highly-specific and regulated sequences wherein successive proteins are activated by cleavage and/or structural changes of the preceding proteins.
• The complement system serves as a marker to indicate targets for phagocytic cells; complement proteins can also combine to form attack complexes capable of opening pores in microbial cell membranes.
Key Terms
• opsonization: the process by which a pathogen is marked for ingestion and destruction by a phagocyte
• complement system: an aspect of the innate immune system that supplements the actions of the antibodies and phagocytic cells in clearing out pathogens from an organism
Complement
The innate immune system serves as a first responder to pathogenic threats that bypass natural physical and chemical barriers of the body. Using a combination of cellular and molecular attacks, the innate immune system identifies the nature of a pathogen and responds with inflammation, phagocytosis (where a cell engulfs a foreign particle), cytokine release, destruction by NK cells, and/or a complement system. In this concept, we will discuss the complement system.
An array of approximately 20 types of soluble proteins, called a complement system, functions to destroy extracellular pathogens. Cells of the liver and macrophages synthesize complement proteins continuously. These proteins are abundant in the blood serum and are capable of responding immediately to infecting microorganisms. The complement system is so named because it is complementary to the antibody response of the adaptive immune system. Complement proteins bind to the surfaces of microorganisms and are particularly attracted to pathogens that are already bound by antibodies. Binding of complement proteins occurs in a specific and highly-regulated sequence, with each successive protein being activated by cleavage and/or structural changes induced upon binding of the preceding protein(s). After the first few complement proteins bind, a cascade of sequential binding events follows in which the pathogen rapidly becomes coated in complement proteins.
Complement proteins perform several functions. They serve as a marker to indicate the presence of a pathogen to phagocytic cells, such as macrophages and B cells, to enhance engulfment. This process is called opsonization. Certain complement proteins can combine to form attack complexes that open pores in microbial cell membranes. These structures destroy pathogens by causing their contents to leak. When innate mechanisms are insufficient to clear an infection, the adaptive immune response is informed and mobilized. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.02%3A_The_Innate_Immune_Response/11.2B%3A_Physical_and_Chemical_Barriers.txt |
Upon pathogen entry to the body, the innate immune system uses several mechanisms to destroy the pathogen and any cells it has infected.
Learning Objectives
• Describe the role of PAMPs and PRRs, interferons, and other cytokines in innate immunity
Key Points
• Pathogens are recognized by a variety of immune cells, such as macrophages and dendritic cells, via pathogen-associated molecular patterns (PAMPs) on the pathogen surface, which interact with complementary pattern-recognition receptors (PRRs) on the immune cells’ surfaces.
• Upon binding of PRRs with PAMPs (pathogen recognition), immune cells release cytokines to tell other cells to start fighting back.
• One class of cytokines, interferons, warn nearby uninfected cells of impending infection, cause cells to start cleaving RNA and reduce protein synthesis, and signal nearby infected cells to undergo apoptosis.
• Another class of cytokines, called inerleukins, mediate interactions between white blood cells ( leukocytes ) and help bridge the innate and adaptive immune responses.
• Inflammation (hot, red, swollen, painful tissue associated with infection) is encouraged by cytokines that are produced immediately upon pathogen recognition; the increase in blood flow associated with inflammation allows more leukocytes (a type of innate immune cell) to reach the infected area.
Key Terms
• macrophage: a white blood cell that phagocytizes necrotic cell debris and foreign material, including viruses, bacteria, and tattoo ink; part of the innate immune system
• phagocytosis: the process where a cell incorporates a particle by extending pseudopodia and drawing the particle into a vacuole of its cytoplasm
• cytokine: any of various small regulatory proteins that regulate the cells of the immune system; they are released upon binding of PRRs to PAMPS
Pathogen recognition
When a pathogen enters the body, cells in the blood and lymph detect the specific pathogen-associated molecular patterns (PAMPs) on the pathogen’s surface. PAMPs are carbohydrate, polypeptide, and nucleic acid “signatures” that are expressed by viruses, bacteria, and parasites, but which differ from molecules on host cells. These PAMPs allow the immune system to recognize “self” from “other” so as not to destroy the host.
The immune system has specific cells with receptors that recognize these PAMPs. A macrophage is a large, phagocytic cell that engulfs foreign particles and pathogens. Macrophages recognize PAMPs via complementary pattern recognition receptors (PRRs). PRRs are molecules on macrophages and dendritic cells which are in contact with the external environment and can thus recognize PAMPs when present. A monocyte, a type of leukocyte (white blood cell) that circulates in the blood and lymph, differentiates into macrophages after it moves into infected tissue. Dendritic cells bind molecular signatures of pathogens, promoting pathogen engulfment and destruction.
Once a pathogen is detected, the immune system must also track whether it is replicating intracellularly (inside the cell, as with most viruses and some bacteria) or extracellularly (outside of the cell, as with other bacteria, but not viruses). The innate immune system must respond accordingly by identifying the extracellular pathogen and/or by identifying host cells that have already been infected.
Cytokine release affect
The binding of PRRs with PAMPs triggers the release of cytokines, which signal that a pathogen is present and needs to be destroyed along with any infected cells. A cytokine is a chemical messenger that regulates cell differentiation (form and function), proliferation (production), and gene expression to affect immune responses. At least 40 types of cytokines exist in humans that differ in terms of the cell type that produces them, the cell type that responds to them, and the changes they produce.
One subclass of cytokines is the interleukin (IL), which mediates interactions between leukocytes (white blood cells). Interleukins are involved in bridging the innate and adaptive immune responses. In addition to being released from cells after PAMP recognition, cytokines are released by the infected cells which bind to nearby uninfected cells, inducing those cells to release cytokines, resulting in a cytokine burst.
A second class of cytokines is interferons, which are released by infected cells as a warning to nearby uninfected cells. A function an interferons is to inhibit viral replication, making them particularly effective against viruses. They also have other important functions, such as tumor surveillance. Interferons work by signaling neighboring uninfected cells to destroy RNA (often a very important biomolecule for viruses) and reduce protein synthesis; signaling neighboring infected cells to undergo apoptosis (programmed cell death); and activating immune cells.
Cytokines also send feedback to cells of the nervous system to bring about the overall symptoms of feeling sick, which include lethargy, muscle pain, and nausea. These effects may have evolved because the symptoms encourage the individual to rest, preventing them from spreading the infection to others. Cytokines also increase the core body temperature, causing a fever, which causes the liver to withhold iron from the blood. Without iron, certain pathogens (such as some bacteria) are unable to replicate; this is called nutritional immunity.
Phagocytosis and inflammation
The first cytokines to be produced are pro-inflammatory; that is, they encourage inflammation, or the localized redness, swelling (edema), heat, loss of function, and pain that result from the movement of leukocytes and fluid through increasingly-permeable capillaries to a site of infection. The population of leukocytes that arrives at an infection site depends on the nature of the infecting pathogen. Both macrophages and dendritic cells engulf pathogens and cellular debris through phagocytosis. A neutrophil is also a phagocytic leukocyte that engulfs and digests pathogens. Neutrophils, the most-abundant leukocytes of the immune system, have a nucleus with two to five lobes and contain organelles (lysosomes) that digest engulfed pathogens. An eosinophil is a leukocyte that works with other eosinophils to surround a parasite. It is involved in the allergic response and in protection against helminthes (parasitic worms).
Neutrophils and eosinophils are particularly important leukocytes that engulf large pathogens, such as bacteria and fungi. A mast cell is a leukocyte that produces inflammatory molecules, such as histamine, in response to large pathogens. A basophil is a leukocyte that, like a neutrophil, releases chemicals to stimulate the inflammatory response. Basophils are also involved in allergy and hypersensitivity responses and induce specific types of inflammatory responses. Eosinophils and basophils produce additional inflammatory mediators to recruit more leukocytes. A hypersensitive immune response to harmless antigens, such as in pollen, often involves the release of histamine by basophils and mast cells; this is why many anti-allergy medications are anti-histamines.
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Learning Objectives
• Summarize phagocytosis and phagocyte migration
Phagocytosis is the process by which a cell takes in particles such as bacteria, parasites, dead host cells, and cellular and foreign debris. It involves a chain of molecular processes. Phagocytosis occurs after the foreign body, a bacterial cell, for example, has bound to molecules called “receptors” that are on the surface of the phagocyte. The phagocyte then stretches itself around the bacterium and engulfs it. Phagocytosis of bacteria by human neutrophils takes on average nine minutes to occur. Once inside the phagocyte, the bacterium is trapped in a compartment called a phagosome. Within one minute the phagosome merges with either a lysosome or a granule, to form a phagolysosome. The bacterium is then subjected to an overwhelming array of killing mechanisms and is dead a few minutes later. Dendritic cells and macrophages, on the other hand, are not so fast, and phagocytosis can take many hours in these cells. Macrophages are slow and untidy eaters; they engulf huge quantities of material and frequently release some undigested material back into the tissues. This debris serves as a signal to recruit more phagocytes from the blood. Phagocytes have voracious appetites; scientists have even fed macrophages with iron filings and then used a small magnet to separate them from other cells.
All phagocytes, and especially macrophages, exist in degrees of readiness. Macrophages are usually relatively dormant in the tissues and proliferate slowly. In this semi-resting state, they clear away dead host cells and other non-infectious debris and rarely take part in antigen presentation. But, during an infection, they receive chemical signals—usually interferon gamma—which increases their production of MHC II molecules and which prepares them for presenting antigens. In this state, macrophages are good antigen presenters and killers. However, if they receive a signal directly from an invader, they become “hyperactivated”, stop proliferating, and concentrate on killing. Their size and rate of phagocytosis increases—some become large enough to engulf invading protozoa. In the blood, neutrophils are inactive but are swept along at high speed. When they receive signals from macrophages at the sites of inflammation, they slow down and leave the blood. In the tissues, they are activated by cytokines and arrive at the battle scene ready to kill.
When an infection occurs, a chemical “SOS” signal is given off to attract phagocytes to the site. These chemical signals may include proteins from invading bacteria, clotting system peptides, complement products, and cytokines that have been given off by macrophages located in the tissue near the infection site. Another group of chemical attractants are cytokines that recruit neutrophils and monocytes from the blood. To reach the site of infection, phagocytes leave the bloodstream and enter the affected tissues. Signals from the infection cause the endothelial cells that line the blood vessels to make a protein called selectin, which neutrophils stick to when they pass by. Other signals called vasodilators loosen the junctions connecting endothelial cells, allowing the phagocytes to pass through the wall. Chemotaxis is the process by which phagocytes follow the cytokine “scent” to the infected spot. Neutrophils travel across epithelial cell-lined organs to sites of infection, and although this is an important component of fighting infection, the migration itself can result in disease-like symptoms. During an infection, millions of neutrophils are recruited from the blood, but they die after a few days.
Key Points
• Phagocytosis is needed to clear many things from a body, especially during an infection, when specialized cells “eat” things such as cellular debris or invading microbes.
• There are different cells that can engulf or phagocytose material in the body, these include macrophages, dendritic cells, and neutrophils.
• Phagocytic cells can migrate to a location where they are needed, through signaling events in the body.
Key Terms
• neutrophil: Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system.
• metachromatic granule: a granular cell inclusion present in many bacterial cells, having an avidity for basic dyes and causing irregular staining of the cell
• macrophage: A white blood cell that phagocytizes necrotic cell debris and foreign material, including viruses, bacteria, and tattoo ink. It presents foreign antigens on MHC II to lymphocytes. Part of the innate immune system. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.03%3A_Phagocytes/11.3A%3A_Phagocyte_Migration_and_Phagocytosis.txt |
Learning Objectives
• Explain the role played by B and T cells in the adaptive immune system
The adaptive, or acquired, immune response to an initial infection takes days or even weeks to become established, much longer than the innate response. However, adaptive immunity is more specific to an invading pathogen and can fight back much more quickly than the innate response if it has seen the pathogen before. Adaptive immunity occurs after exposure to an antigen either from a pathogen or a vaccination. An antigen is a molecule that binds to a specific antibody, often stimulating a response in the immune system as a result.
The adaptive immune response activates when the innate immune response insufficiently controls an infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized. There are two types of adaptive responses: the cell-mediated immune response, which is controlled by activated T cells, and the humoral immune response, which is controlled by activated B cells and antibodies. Upon infection, activated T and B cells that have surface binding sites with specificity to the molecules on the pathogen greatly increase in number and attack the invading pathogen. Their attack can kill pathogens directly or they can secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory, which gives the host long-term protection from reinfection by the same type of pathogen; upon re-exposure, this host memory will facilitate a rapid and powerful response.
B and T Cells
Lymphocytes, which are white blood cells, are formed with other blood cells in the red bone marrow found in many flat bones, such as the shoulder or pelvic bones. The two types of lymphocytes of the adaptive immune response are B and T cells. Whether an immature lymphocyte becomes a B cell or T cell depends on where in the body it matures. The B cells remain in the bone marrow to mature (hence the name “B” for “bone marrow”), while T cells migrate to the thymus, where they mature (hence the name “T” for “thymus”).
B Cell Receptors
The maturation of a B or T cell involves becoming immunocompetent, meaning that it can recognize and bind to a specific molecule or antigen. This recognition, which is central to the functioning of the adaptive immune response, results from the presence of highly specific receptors on the surfaces of B and T cells. On B cells, these receptors contain antibodies, which are responsible for antigen binding. An antibody is specific for one particular antigen; typically, it will not bind to anything else. Upon antigen binding to a B cell receptor, a signal is sent into the B cell to turn on an immune response.
T Cell Receptors
Meanwhile, T cell receptors are responsible for the recognition of pathogenic antigens by T cells. Unlike B cells, T cells do not directly recognize antigens. Instead, they recognize antigens presented on major histocompatibility complexes ( MHCs ) that cells use to display which proteins are inside of them. If a cell is infected, it will present antigenic portions of the infecting pathogen on its MHC for recognition by T cells, which will then mount an appropriate immune response. Unlike antibodies, which can typically bind one and only one antigen, T cell receptors have more flexibility in their capacity to recognize antigens presented by MHCs.
It is the specific pathogen recognition (via binding antigens) of B and T cells that allows the adaptive immune response to adapt. During the maturation process, B and T cells that bind too strongly to the body’s own cells’ antigens are eliminated in order to minimize an immune response against the body’s own tissues. Only those cells that react weakly to the body’s own cells will remain. This process occurs during fetal development and continues throughout life. Once they are immunocompetent, the T and B cells migrate to the spleen and lymph nodes where they remain until they are called on during an infection. B cells are involved in the humoral immune response, which targets pathogens loose in blood and lymph, while T cells are involved in the cell-mediated immune response, which targets infected cells.
Key Points
• The adaptive immune response is slower to develop than the innate immune response, but it can act much more powerfully and quickly than the innate immune response against pathogens that it has seen before.
• B and T cells are lymphocytes, or white blood cells, which are able to recognize antigens that distinguish “self” from “other” in the body.
• B and T cells that recognize “self” antigens are destroyed before they can mature; this helps to prevent the immune system from attacking its own body.
Key Terms
• B cell: a lymphocyte, developed in the bursa of birds and the bone marrow of other animals, that produces antibodies and is responsible for the immune system
• T cell: a lymphocyte, from the thymus, that can recognize specific antigens and can activate or deactivate other immune cells
• antigen: a substance that binds to a specific antibody; may cause an immune response
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The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism.
Learning Objectives
• Illustrate the key points of the complement system
Key Points
• Three biochemical pathways activate the complement system–the classical complement pathway, the alternative complement pathway, and the lectin pathway.
• The following are the basic functions of the complement: Opsonization (enhancing phagocytosis of antigens ); chemotaxis (attracting macrophages and neutrophils); cell lysis (rupturing membranes of foreign cells); and clumping (antigen-bearing agents).
• The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins).
Key Terms
• antibodies: An antibody (Ab), also known as an immunoglobulin (Ig), is a large Y-shaped protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, called an “antigen. “
• phagocytic: Phagocytosis, meaning “cell,” and -osis, meaning “process,” is the cellular process of engulfing solid particles by the cell membrane to form an internal phagosome by phagocytes and protists.
• pathogens: A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host. The host may be an animal (including humans), a plant, or even another microorganism.
• classical pathway: a group of blood proteins that mediate the specific antibody response
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the ” innate immune system ” that is not adaptable and does not change over the course of an individual’s lifetime. However, it can be recruited and brought into action by the adaptive immune system.
The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex. Over 25 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. They account for about 5% of the globulin fraction of blood serum.
Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway. The following are the basic functions of the complement: opsonization (enhancing phagocytosis of antigens); chemotaxis (attracting macrophages and neutrophils); cell lysis (rupturing membranes of foreign cells); and clumping (antigen-bearing agents).
The proteins and glycoproteins that constitute the complement system are synthesized by the liver hepatocytes. But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the genitourinal tract and gastrointestinal tract. The three pathways of activation all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antigen, antibody complexes for activation (specific immune response), whereas the alternative and mannose-binding lectin pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causing a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells by opsonization. C5a is an important chemotactic protein, helping recruit inflammatory cells.
C3a is the precursor of an important cytokine (adipokine) named ASP and is usually rapidly cleaved by carboxypeptidase B. Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells, as well as increasing vascular permeability and smooth muscle contraction. C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9. MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic lysis of the target cell. Kupffer cells and other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates, most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.
n the classical pathway, C1 binds with its C1q subunits to Fc fragments (made of CH2 region) of IgG or IgM, which forms a complex with antigens. C4b and C3b are also able to bind to antigen-associated IgG or IgM, to its Fc portion.
Such immunoglobulin-mediated binding of the complement may be interpreted, as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement itself is able to bind non-self pathogens after detecting their pathogen-associated molecular patterns (PAMPs); however, utilizing specificity of antibody, complements are able to detect non-self enemies much more specifically. There must be mechanisms that complements bind to Ig but would not focus its function to Ig but to the antigen.
shows the classical and the alternative pathways with the late steps of complement activation schematically. Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and C1r2s2 enzyme cleaves C4 to C4b and 4a. C4b binds to C1q, antigen-associated Ig (specifically to its Fc portion), and even to the microbe surface. C3b binds to antigen-associated Ig and to the microbe surface. The ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody immune complexes to make them soluble. In the figure, C2b refers to the larger of the C2 fragments. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.04%3A_Innate_Defenders/11.4A%3A_The_Complement_System.txt |
Learning Objectives
• Identify interferons and their effects
Interferons (IFNs) are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites, or tumor cells. IFNs belong to the large class of glycoproteins known as cytokines. Interferons are named after their ability to “interfere” with viral replication within host cells. IFNs have other functions: they activate immune cells, such as natural killer cells and macrophages, they increase recognition of infection or tumor cells by up-regulating antigen presentation to T lymphocytes, and they increase the ability of uninfected host cells to resist new infection by virus. Certain symptoms, such as aching muscles and fever, are related to the production of IFNs during infection.
About ten distinct IFNs have been identified in mammals; seven of these have been described for humans. They are typically divided among three IFN classes: type I IFN, type II IFN, and type III IFN. IFNs belonging to all IFN classes are very important for fighting viral infections.
Based on the type of receptor through which they signal, human interferons have been classified into three major types:
• Interferon type I: All type I IFNs bind to a specific cell surface receptor complex, known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-α, IFN-β and IFN-ω.
• Interferon type II: These bind to IFNGR that consist of IFNGR1 and IFNGR2 chains. In humans this is IFN-γ.
• Interferon type III: These signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Acceptance of this classification is less universal than that of type I and type II, and unlike the other two, it is not currently included in Medical Subject Headings.
Effects of Interferons
All interferons share several common effects; they are antiviral agents and can fight tumors. As an infected cell dies from a cytolytic virus, viral particles are released that can infect nearby cells. In addition, interferons induce production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)—that have roles in combating viruses. They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis. The effect of IFN on p53 is also linked to its protective role against certain cancers. Another function of interferons is to upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Interferons, such as interferon gamma, directly activate other immune cells, such as macrophages and natural killer cells. Interferons can inflame the tongue and cause dysfunction in taste bud cells, restructuring or killing taste buds entirely.
By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT) complexes. STATs are a family of transcription factors that regulate the expression of certain immune system genes. Some STATs are activated by both type I and type II IFNs. However, each IFN type can also activate unique STATs.
STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical Janus kinase-STAT (JAK-STAT) signaling pathway. In this pathway, JAKs associate with IFN receptors and, following receptor engagement with IFN, phosphorylate both STAT1 and STAT2. As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms—this contains STAT1, STAT2 and a third transcription factor called IRF9—and moves into the cell nucleus. Inside the nucleus, the ISGF3 complex binds to specific nucleotide sequences called IFN-stimulated response elements (ISREs) in the promoters of certain genes, known as IFN stimulated genes ISGs. Binding of ISGF3 and other transcriptional complexes activated by IFN signaling to these specific regulatory elements induces transcription of those genes. Interferome is a curated online database of ISGs (www.interferome.org). Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimers initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters. Type I IFNs can induce expression of genes with either ISRE or GAS elements, but gene induction by type II IFN can occur only in the presence of a GAS element.
In addition to the JAK-STAT pathway, IFNs can activate several other signaling cascades. Both type I and type II IFNs activate a member of the CRK family of adaptor proteins called CRKL, a nuclear adaptor for STAT5 that also regulates signaling through the C3G/Rap1 pathway. Type I IFNs further activate p38 mitogen-activated protein kinase (MAP kinase) to induce gene transcription. Antiviral and antiproliferative effects specific to type I IFNs result from p38 MAP kinase signaling. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is also regulated by both type I and type II IFNs. PI3K activates P70-S6 Kinase 1, an enzyme that increases protein synthesis and cell proliferation; phosphorylates of ribosomal protein s6, which is involved in protein synthesis; and phosphorylates a translational repressor protein called eukaryotic translation-initiation factor 4E-binding protein 1 (EIF4EBP1) in order to deactivate it.
Key Points
• Interferons are named after their ability to “interfere” with viral replication within host cells.
• IFNs are divided into three classes: type I IFN, type II IFN, and type III IFNs.
• IFNs activate immune cells (natural killer cells and macrophages ), increase recognition of infection and tumor cells by up-regulating antigen presentation to T lymphocytes, and increase the ability of uninfected host cells to resist new infection by virus.
Key Terms
• Interferons: Interferons (IFNs) are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites or tumor cells. They allow for communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.
• pathogens: A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host. The host may be an animal (including humans), a plant, or even another microorganism.
• immune cells: White blood cells, or leukocytes, are cells of the immune system involved in defending the body against both infectious disease and foreign materials. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.04%3A_Innate_Defenders/11.4B%3A_Interferons.txt |
Learning Objectives
• Describe natural killer cells
Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte critical to the innate immune system. The role NK cells play is similar to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virally infected cells and to tumor formation, beginning around three days after infection. Typically immune cells detect MHC that is present on infected cell surfaces, triggering cytokine release and causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named “natural killers” because of the initial notion that they do not require activation in order to kill cells that are missing “self” markers of major histocompatibility complex (MHC) class 1.
NK cells are defined as large granular lymphocytes (LGL) and constitute the third kind of cell differentiated from the common lymphoid progenitor generating B and T lymphocytes. NK cells are known to differentiate and mature in the bone marrow, lymph node, spleen, tonsils, and thymus, where they then enter into the circulation. NK cells differ from Natural Killer T cells (NKT) phenotypically, by origin, and by respective effector functions. Often NKT cell activity promotes NK cell activity by secreting IFNγ. In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or Pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans, NK1.1 or NK1.2 in C57BL/6 mice. Up to 80% of human NK cells also express CD8.
Mechanism
NK cells paralyze target cells using the cytolytic protein perforin and a variety of protease enzymes. An NK cell will first use perforin to create pores in a target cell, allowing it to inject granzymes through an aqueous channel. The granzymes then break down the target cell, inducing death by either apoptosis or osmotic cell lysis.
NK cells also alert the greater immune system by secreting chemicals that are taken as a message that a threat has arrived.
Natural Killer Cells Play Other Roles
Natural killer cells are not only effectors of innate immunity; recent research has also uncovered information on both activating and inhibitory NK cell receptors, which play roles in maintaining self-tolerance and sustaining NK cell activity. NK cells also play a role in the adaptive immune response. Numerous experiments have demonstrated their ability to adjust to the immediate environment and formulate antigen-specific immunological memory, which is fundamental for responding to secondary infections with the same antigen. The ability for NK cells to act in both innate and adaptive immune response is becoming increasingly important in research utilizing NK cell activity in potential cancer therapies.
NK cell receptors can also be differentiated based on function. Natural cytotoxicity receptors directly induce apoptosis after binding to ligands that directly indicate infection of a cell. The MHC dependent receptors (described above) use an alternate pathway to induce apoptosis in infected cells. Natural killer cell activation is determined by the balance of inhibitory and activating receptor stimulation—for example, if the inhibitory receptor signaling is more prominent, then NK cell activity will be inhibited. Similarly, if the activating signal is dominant, then NK cell activation will result.
Functions of NK cells include: Cytolytic Granule Mediated Cell Apoptosis; Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC); Cytokine induced NK and CTL activation; Missing ‘self’ hypothesis; Tumor cell surveillance; NK cell function in adaptive response; NK cell function in pregnancy; and NK cell evasion by tumor cells.
Key Points
• NK cells are defined as large granular lymphocytes (LGL).
• NK cells constitute the third kind of cells differentiated from the common lymphoid progenitor generating B and T lymphocytes.
• NK cells provide rapid responses to virally infected cells and respond to tumor formation, acting at around 3 days after infection.
Key Terms
• Natural killer cells (or NK cells): Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte critical to the innate immune system. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response.
• lymphocyte: A type of white blood cell or leukocyte that is divided into two principal groups and a null group: B-lymphocytes, which produce antibodies in the humoral immune response, T-lymphocytes, which participate in the cell-mediated immune response, and the null group, which contains natural killer cells, cytotoxic cells that participate in the innate immune response.
• innate immune system: This is the initial line of defense that entails a cascade of cells and mechanisms that protect the host from infection by different organisms in an indeterminate pattern. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.04%3A_Innate_Defenders/11.4C%3A__Natural_Killer_Cells.txt |
Learning Objectives
• Summarize Toll-like receptors
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system as well as the digestive system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses.
TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). TLRs together with the Interleukin-1 receptors form a receptor superfamily, known as the “Interleukin-1 Receptor/Toll-Like Receptor Superfamily”; all members of this family have in common a so-called TIR (Toll-IL-1 receptor) domain.
Because of the specificity of Toll-like receptors (and other innate immune receptors) they cannot easily be changed in the course of evolution, these receptors recognize molecules that are constantly associated with threats (i.e., pathogen or cell stress) and are highly specific to these threats (i.e., cannot be mistaken for self molecules). Pathogen-associated molecules that meet this requirement are usually critical to the pathogen’s function and cannot be eliminated or changed through mutation; they are said to be evolutionarily conserved. Well-conserved features in pathogens include bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, lipopeptides, and lipoarabinomannan; proteins such as flagellin from bacterial flagella; double-stranded RNA of viruses; or the unmethylated CpG islands of bacterial and viral DNA; and certain other RNA and DNA. For most of the TLRs, ligand recognition specificity has now been established by gene targeting (also known as “gene knockout”): a technique by which individual genes may be selectively deleted in mice. See the table below for a summary of known TLR ligands.
TLRs are believed to function as dimers. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand specificity. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4’s recognition of LPS, which requires MD-2. CD14 and LPS-Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.
The adapter proteins and kinases that mediate TLR signaling have also been targeted. In addition, random germline mutagenesis with ENU has been used to decipher the TLR signaling pathways. When activated, TLRs recruit adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adapter molecules are known to be involved in signaling. These proteins are known as MyD88, Tirap (also called Mal), Trif, and Tram.
TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway. The MyD88-dependent response occurs on dimerization of the TLR receptor, and is utilized by every TLR except TLR3. Its primary effect is activation of NFκB. Ligand binding and conformational change that occurs in the receptor recruits the adaptor protein MyD88, a member of the TIR family. MyD88 then recruits IRAK 4, IRAK1 and IRAK2. IRAK kinases then phosphorylate and activate the protein TRAF6, which in turn polyubiquinates the protein TAK1, as well as itself in order to facilitate binding to IKKβ. On binding, TAK1 phosphorylates IKKβ, which then phosphorylates IκB causing its degradation and allowing NFκB to diffuse into the cell nucleus and activate transcription.
Both TRL3 and TRL4 utilize the TRIF-dependent pathway, which is triggered by dsRNA and LPS, respectively. For TRL3, dsRNA leads to activation of the receptor, recruiting the adaptor TRIF. TRIF activates the kinases TBK1 and RIP1, which creates a branch in the signaling pathway. The TRIF/TBK1 signaling complex phosphorylates IRF3 allowing its translocation into the nucleus and production of Type I interferons. Meanwhile, activation of RIP1 causes the polyubiquination and activation of TAK1 and NFκB transcription in the same manner as the MyD88-dependent pathway.
TLR signaling ultimately leads to the induction or suppression of genes that orchestrate the inflammatory response. In all, thousands of genes are activated by TLR signaling, and collectively, the TLRs constitute one of the most pleiotropic yet tightly regulated gateways for gene modulation.
Toll-like receptors bind and become activated by different ligands, which, in turn, are located on different types of organisms or structures. They also have different adapters to respond to activation and are located sometimes at the cell surface and sometimes to internal cell compartments.
Key Points
• TLRs are a type of pattern recognition receptor (PRR).
• TLRs recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs).
• TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway.
Key Terms
• Toll-like receptor: Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system as well as the digestive system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes.
• innate immune system: This is the initial line of defense that entails a cascade of cells and mechanisms that protect the host from infection by different organisms in an indeterminate pattern.
• signaling pathway: Signal pathways occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response. There are two stages in this process:A signaling molecule activates a specific receptor protein on the cell membrane.A second messenger transmits the signal into the cell, eliciting a physiological response.In either step, the signal can be amplified. Thus, one signaling molecule can cause many responses.
11.4E: Iron-Binding Proteins
Iron binding proteins of the innate immune system include lactoferrin and transferrins.
Learning Objectives
• Describe Iron-Binding proteins
Key Points
• Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family.
• Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids such as milk, saliva, tears, and nasal secretions.
• Transferrins are iron -binding blood plasma glycoproteins that control the level of free iron in biological fluids.
Key Terms
• transferrin: A glycoprotein, a beta globulin, in blood serum that combines with and transports iron
• Lactoferrin: Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa. It is widely represented in various secretory fluids such as milk, saliva, tears, and nasal secretions.
• iron: Iron is a chemical element with the symbol Fe (from Latin: ferrum) and atomic number 26. It is a metal in the first transition series.
Iron-binding proteins are proteins generally used to play roles in metabolism. They are carrier proteins (those used to move ions and molecules across membranes) and more generally metalloproteins (those which contain a metal ion cofactor). Iron-binding proteins are serum proteins, found in the blood, and as their name suggests, are used to bind and transport iron.
Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa. It is widely represented in various secretory fluids such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMN (Polymorphonucler neutrophil) and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum (“first milk”) has the highest concentration, followed by human milk, and then cow milk (150 mg/L).
Lactoferrin is one of the components of the immune system of the body. It has antimicrobial activity (bacteriocide, fungicide) and is part of the innate defense, mainly at mucoses. In particular, lactoferrin provides antibacterial activity to human infants. Lactoferrin interacts with DNA and RNA, polysaccharides and heparin, and shows some of its biological functions in complexes with these ligands.
Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. Human transferrin is encoded by the TF gene. Transferrin glycoproteins bind iron very tightly, but reversibly. Although iron bound to transferrin is less than 0.1% (4 mg) of the total body iron, it is the most important iron pool, with the highest rate of turnover (25 mg/24 h). Transferrin has a molecular weight of around 80 KDa and contains two specific high- affinity Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (1023 M−1 at pH 7.4), but decreases progressively with decreasing pH below neutrality. When not bound to iron, it is known as “apotransferrin” (see also apoprotein). | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.04%3A_Innate_Defenders/11.4D%3A_Toll-Like_Receptors.txt |
Antimicrobial peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life.
Learning Objectives
• Describe the role of antimicrobial peptides in host defense
Key Points
• Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure.
• The modes of action by which antimicrobial peptides kill bacteria is varied and includes disrupting membranes, interfering with metabolism, and targeting cytoplasmic components.
• Antimicrobial peptides have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection.
Key Terms
• antimicrobial peptide: Antimicrobial peptides (also called host defense peptides) are an evolutionarily conserved component of the innate immune response and are found among all classes of life.
• innate immune: The innate immune system, also known as non-specific immune system and first line of defense, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. This means that the cells of the innate system recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host.
• molecules: A molecule is an electrically neutral group of two or more atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their lack of electrical charge. However, in quantum physics, organic chemistry, and biochemistry, the term molecule is often used less strictly, also being applied to polyatomic ions.
Antimicrobial peptides (also called host defense peptides) are an evolutionarily conserved component of the innate immune response and are found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria (including strains that are resistant to conventional antibiotics), mycobacteria (including Mycobacterium tuberculosis), enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics, it appears as though antimicrobial peptides may also have the ability to enhance immunity by functioning as immunomodulators.
Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure. Antimicrobial peptides generally consist of between 12 and 50 amino acids. These peptides include two or more positively charged residues provided by arginine, lysine or, in acidic environments, histidine, and a large proportion (generally >50%) of hydrophobic residues. The secondary structures of these molecules follow 4 themes, including:
Various AMPs: These are various antimicrobial peptide structures.
1. α-helical
2. β-stranded due to the presence of 2 or more disulfide bonds
3. β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain
4. Extended
Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. It contains hydrophilic amino acid residues aligned along one side and hydrophobic amino acid residues aligned along the opposite side of a helical molecule. This amphipathicity of the antimicrobial peptides allows the partition of the membrane lipid bilayer. The ability to associate with membranes is a definitive feature of antimicrobial peptides, although membrane permeabilisation is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets.
The modes of action by which antimicrobial peptides kill bacteria is varied and includes disrupting membranes, interfering with metabolism, and targeting cytoplasmic components. The initial contact between the peptide and the target organism is electrostatic, as most bacterial surfaces are anionic, or hydrophobic, such as in the antimicrobial peptide Piscidin. Their amino acid composition, amphipathicity, cationic charge, and size allow them to attach to and insert into membrane bilayers to form pores by ‘barrel-stave’, ‘carpet’ or ‘toroidal-pore’ mechanisms. Alternately, they may penetrate into the cell to bind intracellular molecules which are crucial to cell living. Intracellular binding models include inhibition of cell wall synthesis, alteration of the cytoplasmic membrane, activation of autolysin, inhibition of DNA, RNA, and protein synthesis, and inhibition of certain enzymes. However, in many cases, the exact mechanism of killing is not known. One emerging technique for the study of such mechanisms is dual polarisation interferometry. In contrast to many conventional antibiotics these peptides appear to be bacteriocidal (bacteria killing) instead of bacteriostatic (bacteria growth inhibiting). In general the antimicrobial activity of these peptides is determined by measuring the minimal inhibitory concentration (MIC), which is the lowest concentration of drug that inhibits bacterial growth.
In addition to killing bacteria directly, they have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection, including the ability to:
• Alter host gene expression
• Act as chemokines and/or induce chemokine production,
• Inhibit lipopolysaccharide induced pro-inflammatory cytokine production
• Promote wound healing
• Modulate the responses of dendritic cells and cells of the adaptive immune response
Animal models indicate that host defense peptides are crucial for both prevention and clearance of infection. It appears as though many peptides initially isolated and termed as “antimicrobial peptides” have been shown to have more significant alternative functions in vivo (e.g. hepcidin).
Several methods have been used to determine the mechanisms of antimicrobial peptide activity. In particular, solid-state NMR studies have provided an atomic-level resolution explanation of membrane disruption by antimicrobial peptides. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.04%3A_Innate_Defenders/11.4F%3A_Antimicrobial_Peptides.txt |
In autoimmune heart diseases, the body’s immune defense system mistakes its own cardiac antigens as foreign, and attacks them.
Learning Objectives
• Identify autoimmune heart diseases
Key Points
• The commonest form of autoimmune heart disease is rheumatic heart disease, or rheumatic fever.
• The typical mechanism of autoimmunity involves auto-toxic T-lymphocyte, and the complement system.
• Inflammatory damage leads to the following: pericarditis, myocarditis, and endocarditis.
Key Terms
• autoimmune: Autoimmunity is the failure of an organism in recognizing its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Autoimmunity is often caused by a lack of germ development of a target body, and as such the immune response acts against its own cells and tissues.
• immune: Immunity is a biological term that describes a state of having sufficient biological defences to avoid infection, disease, or other unwanted biological invasion. In other words, it is the capability of the body to resist harmful microbes from entering it. Immunity involves both specific and non-specific components.
• antigen: A substance that induces an immune response, usually foreign.
Causes
Autoimmune heart diseases result when the body’s own immune defense system mistakes cardiac antigens as foreign, and attacks them, leading to inflammation of the heart as a whole, or in parts. The most common form of autoimmune heart disease is rheumatic heart disease, or rheumatic fever.
A typical mechanism of autoimmunity is autoantibodies, or auto-toxic T-lymphocyte mediated tissue destruction. The process is aided by neutrophils, the complement system, and tumor necrosis factor alpha.
Aetiologically, autoimmune heart disease is most commonly seen in children with a history of sore throat caused by a streptococcal infection. This is similar to the post-streptococcal glomerulonephritis. Here, the anti-bacterial antibodies cross react with the heart antigens causing inflammation.
Pericarditis, Myocarditis, and Endocarditis
Inflammatory damage can lead to pericarditis, myocarditis, and endocarditis.
Pericarditis: Here the pericardium gets inflamed. Acutely, it can cause pericardial effusion leading to cardiac tamponade and death. After healing, there may be fibrosis and adhesion of the pericardium with the heart, leading to constriction of the heart and reduced cardiac function.
Myocarditis: Here the muscle bulk of the heart gets inflamed. Inflamed muscles have reduced functional capacity. This may be fatal if left untreated, as is in a case of pancarditis. On healing, there will be fibrosis and reduced functional capacity.
Endocarditis: Here the inner lining of the heart is inflamed, including the heart valves. This may cause a valve prolapse, adhesion of the adjacent cusps, of these valves, and occlusion of the flow tracts of blood through the heart, which causes disease known as valve stenosis.
Treatment
Specific clinical manifestations depend on the amount of inflammation. Therapy will involve intensive cardiac care and immunosuppressives, including corticosteroids, which are helpful in the acute stage of the disease. The chronic phase consists of mainly debility control and supportive care options.
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The humoral immune response defends against pathogens that are free in the blood by using antibodies against pathogen-specific antigens.
Learning Objectives
• Summarize the humoral immune response
Key Points
• Antigens are proteins and other macromolecules that bind to a specific antibody and are used by the immune system to recognize pathogens.
• B cells express receptors (BCRs) on their membrane which contain antibodies; these antibodies allow B cells to detect pathogens and release further antibodies to fight the infection.
• Antibodies fight infections in three ways: they mark pathogens for destruction by phagocytic cells in a process known as opsonization, they coat key sites on pathogens necessary for infection, and they induce the complement cascade to occur against antibody-bound pathogens.
• Once the adaptive immune response has encountered an antigen, B cells will divide to produce plasma cells, which rapidly secrete antibodies to that antigen in a process called active immunity.
Key Terms
• antibody: a protein produced by B-lymphocytes that binds to a specific antigen
• opsonize: to make (bacteria or other cells) more susceptible to the action of phagocytes by use of opsonins
• MHC: an acronym for major histocompatibility complex; these extracellular protein receptors display antigens derived from extracellular (class I) or intracellular (class II) proteins and other biomolecules
The humoral immune response fights pathogens that are free in the bodily fluids, or “humours”. It relies on antigens (which are also often free in the humours) to detect these pathogens. An antigen is a biomolecule, such as a protein or sugar, that binds to a specific antibody. An antibody/antigen interaction may stimulate an immune response. Not every biomolecule is antigenic and not all antigens produce an immune response. B cells are the major cell type involved in the humoral immune response. When a foreign antigen (one coming from a pathogen, for example) is detected, B cells in the body that recognize that antigen will begin to produce antibodies as a means of fighting off the foreign invader.
B cell maturation
During maturation, B cells gain antigen receptor molecules, termed B cell receptors (BCRs), which are displayed in large numbers, extracellularly on their membrane. These membrane-bound protein complexes contain antibodies, which enable specific antigen recognition. Each B cell initially produced has only one kind of antibody (antigen receptor), which makes every B cell unique. It is the immense number of B cells in the body, each of which produces a unique antibody, that allows the immune system to detect such a wide variety of pathogenic antigens. B cells containing antibodies that recognize “self” antigens are destroyed before they can mature, preventing the immune system from attacking the host. Once B cells mature in the bone marrow, they migrate to lymph nodes or other lymphatic organs, where they may begin to encounter pathogens.
B cell activation
When a B cell encounters the antigen that binds to its receptor, the antigen molecule is brought into the cell by endocytosis, reappearing on the surface of the cell bound to an MHC class II molecule. When this process is complete, the B cell is sensitized. In most cases, the sensitized B cell must then encounter a specific kind of T cell, called a helper T cell, before it is activated. This activation of the helper T cell occurs when a dendritic cell presents an antigen on its MHC II molecule, allowing the T cell to recognize it and mature.
The helper T cell binds to the antigen-MHC class II complex and is induced to release cytokines that induce the B cell to divide rapidly, making thousands of identical (clonal) cells. These daughter cells become either plasma cells or memory B cells. The memory B cells remain inactive at this point. A later encounter with the antigen, caused by a reinfection by the same bacteria or virus, will result in them dividing into a new population of plasma cells. The plasma cells, on the other hand, produce and secrete large quantities, up to 100 million molecules per hour, of antibody molecules. An antibody, also known as an immunoglobulin (Ig), is a protein that is produced by plasma cells after stimulation by an antigen. Antibodies are the agents of humoral immunity. Antibodies occur in the blood, in gastric and mucus secretions, and in breast milk. Antibodies in these bodily fluids can bind pathogens and mark them for destruction by phagocytes before they are able to infect cells.
Antibodies
These antibodies circulate in the blood stream and lymphatic system, binding with the antigen whenever it is encountered. The binding can fight infection in several ways. Antibodies can bind to viruses or bacteria, which interferes with the chemical interactions required for them to infect or bind to other cells. The antibodies may create bridges between different particles containing antigenic sites, clumping them all together and preventing their proper functioning. Antibody neutralization can prevent pathogens from entering and infecting host cells. The neutralized antibody-coated pathogens can then be filtered by the spleen to be eliminated in urine or feces. The antigen-antibody complex stimulates the complement system described previously, destroying the cell bearing the antigen. Antibodies also opsonize pathogen cells, wherein they mark them for destruction by phagocytic cells, such as macrophages or neutrophils. Additionally, antibodies stimulate inflammation, while their presence in mucus and on the skin prevents pathogen attack.
The production of antibodies by plasma cells in response to an antigen is called active immunity. This describes the host’s active response of the immune system to an infection or to a vaccination. There is also a passive immune response wherein antibodies are introduced into the host from an outside source, instead of the individual’s own plasma cells. For example, antibodies circulating in a pregnant woman’s body move across the placenta into the developing fetus. The child benefits from the presence of these antibodies for up to several months after birth. In addition, a passive immune response is possible by injecting antibodies into an individual in the form of an antivenom to a snake-bite toxin or antibodies in blood serum to help fight a hepatitis infection, giving immediate relief. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.05%3A_The_Adaptive_Immune_Response/11.5A%3A_Humoral_Immune_Response.txt |
Lymphocytes originate from a common progenitor in a process known as hematopoeisis.
Learning Objectives
• Examine dual lymphocyte development
Key Points
• B cells and T cells are the major types of lymphocytes.
• B cells mature into B lymphocytes in the bone marrow, while T cells migrate to, and mature in, a distinct organ called the thymus.
• Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs (e.g. the spleen and lymph nodes) where they survey for invading pathogens and/or tumor cells.
• The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to an antigen to form effector and memory lymphocytes.
Key Terms
• lymphocyte: A type of white blood cell or leukocyte that is divided into two principal groups and a null group: B-lymphocytes, which produce antibodies in the humoral immune response, T-lymphocytes, which participate in the cell-mediated immune response, and the null group, which contains natural killer cells, cytotoxic cells that participate in the innate immune response.
• leukocyte: A white blood cell.
• haematopoiesis: Hematopoeisis is the formation of blood cellular components from a common progenitor stem cell.
The cells of the adaptive immune system are a type of leukocyte, called a lymphocyte. The human body has about 2 trillion lymphocytes, constituting 20-40% of white blood cells (WBCs); their total mass is about the same as the brain or liver. The peripheral blood contains 20–50% of circulating lymphocytes; the rest move within the lymphatic system. B cells and T cells are the major types of lymphocytes.
B Cell and T Cell Differentiation
Mammalian stem cells differentiate into several kinds of blood cell within the bone marrow. This process is called haematopoiesis. During this process, all lymphocytes originate from a common lymphoid progenitor before differentiating into their distinct lymphocyte types. The differentiation of lymphocytes into distinguishable types follows various pathways in a hierarchical fashion as well as in a more plastic fashion. The formation of lymphocytes is known as lymphopoiesis. B cells mature into B lymphocytes in the bone marrow, while T cells migrate to, and mature in, a distinct organ called the thymus. Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs (e.g. the spleen and lymph nodes) where they survey for invading pathogens and/or tumor cells.
Further Differentiation
The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to an antigen; they form effector and memory lymphocytes. Effector lymphocytes function to eliminate the antigen, either by releasing antibodies (in the case of B cells), cytotoxic granules (cytotoxic T cells) or by signaling to other cells of the immune system (helper T cells). Memory cells remain in the peripheral tissues and circulation for an extended time ready to respond to the same antigen upon future exposure.
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Immunodeficiency occurs when the immune system cannot appropriately respond to infections.
Learning Objectives
• Explain the problems associated with immunodeficiency
Key Points
• If a pathogen is allowed to proliferate to certain levels, the immune system can become overwhelmed; immunodeficiency occurs when the immune system fails to respond sufficiently to a pathogen.
• Immunodeficiency can be caused by many factors, including certain pathogens, malnutrition, chemical exposure, radiation exposure, or even extreme stress.
• HIV is a virus that causes immunodeficiency by infecting helper T cells, causing cytotoxic T cells to destroy them.
Key Terms
• phagocyte: a cell of the immune system, such as a neutrophil, macrophage or dendritic cell, that engulfs and destroys viruses, bacteria, and waste materials
• lysis: the disintegration or destruction of cells
• immunodeficiency: a depletion in the body’s natural immune system, or in some component of it
Immunodeficiency
Failures, insufficiencies, or delays at any level of the immune response can allow pathogens or tumor cells to gain a foothold to replicate or proliferate to high enough levels that the immune system becomes overwhelmed, leading to immunodeficiency; it may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including certain medical treatments), malnutrition, or, possibly, by extreme stress. For instance, radiation exposure can destroy populations of lymphocytes, elevating an individual’s susceptibility to infections and cancer. Dozens of genetic disorders result in immunodeficiencies, including Severe Combined Immunodeficiency (SCID), bare lymphocyte syndrome, and MHC II deficiencies. Rarely, primary immunodeficiencies that are present from birth may occur. Neutropenia is one form in which the immune system produces a below-average number of neutrophils, the body’s most abundant phagocytes. As a result, bacterial infections may go unrestricted in the blood, causing serious complications.
HIV/AIDS
Human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS), is a disease of the human immune system caused by infection with human immunodeficiency virus (HIV). During the initial infection, a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses, it interferes more and more with the immune system. The person has a high probability of becoming infected, including from opportunistic infections and tumors that do not usually affect people who have working immune systems.
After the virus enters the body, there is a period of rapid viral replication, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood. This response is accompanied by a marked drop in the number of circulating CD4+ T cells, cells that are or will become helper T cells. The acute viremia, or spreading of the virus, is almost invariably associated with activation of CD8+ T cells (which kill HIV-infected cells) and, subsequently, with antibody production. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts recover.
Ultimately, HIV causes AIDS by depleting CD4+ T cells (helper T cells). This weakens the immune system, allowing opportunistic infections. T cells are essential to the immune response; without them, the body cannot fight infections or kill cancerous cells. The mechanism of CD4+ T cell depletion differs in the acute and chronic phases. During the acute phase, HIV-induced cell lysis and killing of infected cells by cytotoxic T cells accounts for CD4+ T cell depletion, although apoptosis (programmed cell death) may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of the ability of the immune system to generate new T cells appear to account for the slow decline in CD4+ T cell numbers. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.06%3A_Antigens_and_Antibodies/11.6A%3A_Immunodeficiency.txt |
Antibodies, part of the humoral immune response, are involved in pathogen detection and neutralization.
Learning Objectives
• Differentiate among affinity, avidity, and cross-reactivity in antibodies
Key Points
• Antibodies are produced by plasma cells, but, once secreted, can act independently against extracellular pathogen and toxins.
• Antibodies bind to specific antigens on pathogens; this binding can inhibit pathogen infectivity by blocking key extracellular sites, such as receptors involved in host cell entry.
• Antibodies can also induce the innate immune response to destroy a pathogen, by activating phagocytes such as macrophages or neutrophils, which are attracted to antibody-bound cells.
• Affinity describes how strongly a single antibody binds a given antigen, while avidity describes the binding of a multimeric antibody to multiple antigens.
• A multimeric antibody may have individual arms with low affinity, but have high overall avidity due to synergistic effects between binding sites.
• Cross reactivity occurs when an antibody binds to a different-but-similar antigen than the one for which it was raised; this can increase pathogen resistance or result in an autoimmune reaction.
Key Terms
• avidity: the measure of the synergism of the strength individual interactions between proteins
• affinity: the attraction between an antibody and an antigen
Antibody Functions
Differentiated plasma cells are crucial players in the humoral immunity response. The antibodies they secrete are particularly significant against extracellular pathogens and toxins. Once secreted, antibodies circulate freely and act independently of plasma cells. Sometimes, antibodies can be transferred from one individual to another. For instance, a person who has recently produced a successful immune response against a particular disease agent can donate blood to a non-immune recipient, confering temporary immunity through antibodies in the donor’s blood serum. This phenomenon, called passive immunity, also occurs naturally during breastfeeding, which makes breastfed infants highly resistant to infections during the first few months of life.
Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the pathogen that enhance their infectivity, such as receptors that “dock” pathogens on host cells. Antibody neutralization can prevent pathogens from entering and infecting host cells, as opposed to the cytotoxic T-cell-mediated approach of killing cells that are already infected to prevent progression of an established infection. The neutralized antibody-coated pathogens can then be filtered by the spleen and eliminated in urine or feces.
Antibodies also mark pathogens for destruction by phagocytic cells, such as macrophages or neutrophils, because they are highly attracted to macromolecules complexed with antibodies. Phagocytic enhancement by antibodies is called opsonization. In another process, complement fixation, IgM and IgG in serum bind to antigens, providing docking sites onto which sequential complement proteins can bind. The combination of antibodies and complement enhances opsonization even further, promoting rapid clearing of pathogens.
Affinity, avidity, and cross reactivity
Not all antibodies bind with the same strength, specificity, and stability. In fact, antibodies exhibit different affinities (attraction) depending on the molecular complementarity between antigen and antibody molecules. An antibody with a higher affinity for a particular antigen would bind more strongly and stably. It would be expected to present a more challenging defense against the pathogen corresponding to the specific antigen.
The term avidity describes binding by antibody classes that are secreted as joined, multivalent structures (such as IgM and IgA). Although avidity measures the strength of binding, just as affinity does, the avidity is not simply the sum of the affinities of the antibodies in a multimeric structure. The avidity depends on the number of identical binding sites on the antigen being detected, as well as other physical and chemical factors. Typically, multimeric antibodies, such as pentameric IgM, are classified as having lower affinity than monomeric antibodies, but high avidity. Essentially, the fact that multimeric antibodies can bind many antigens simultaneously balances their slightly-lower-binding strength for each antibody/antigen interaction.
Antibodies secreted after binding to one epitope on an antigen may exhibit cross reactivity for the same or similar epitopes on different antigens. Cross reactivity occurs when an antibody binds not to the antigen that elicited its synthesis and secretion, but to a different antigen. Because an epitope corresponds to such a small region (the surface area of about four to six amino acids), it is possible for different macromolecules to exhibit the same molecular identities and orientations over short regions.
Cross reactivity can be beneficial if an individual develops immunity to several related pathogens despite having been exposed to or vaccinated against only one of them. For instance, antibody cross reactivity may occur against the similar surface structures of various Gram-negative bacteria. Conversely, antibodies raised against pathogenic molecular components that resemble self molecules may incorrectly mark host cells for destruction, causing autoimmune damage. Patients who develop systemic lupus erythematosus (SLE) commonly exhibit antibodies that react with their own DNA. These antibodies may have been initially raised against the nucleic acid of microorganisms, but later cross-reacted with self-antigens. This phenomenon is also called molecular mimicry.
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A region at the tip of the antibody protein is very variable, allowing millions of antibodies with different antigen-binding sites to exist.
Learning Objectives
• Describe the general function and structure of an antibody
Key Points
• An antibody (Ab), also known as an immunoglobulin (Ig), is a large protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, called an antigen.
• Each tip of the “Y” of an antibody contains a paratope that is specific for one particular epitope (analogous to a lock and key) on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell.
• The general structure of all antibodies is very similar: The Ig monomer is a Y-shaped molecule that consists of four polypeptide chains: two identical heavy chains and two identical light chains connected by disulphide bonds.
• Antibodies can occur in two physical forms, a soluble form that is secreted from the cell, and a membrane-bound form that is attached to the surface of a B-cell and is referred to as the B-cell receptor (BCR).
Key Terms
• Hypervariable region: In antibodies, hypervariable regions form the antigen-binding site and are found on both light and heavy chains. They also contribute to the specificity of each antibody. In a variable region, the 3 HV segments of each heavy or light chain fold together at the N-terminus to form an antigen binding pocket.
An antibody (Ab), also known as an immunoglobulin (Ig), is a large Y-shaped protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, called an antigen. Each tip of the “Y” of an antibody contains a paratope (a structure analogous to a lock) that is specific for one particular epitope (similarly analogous to a key) on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe, or an infected cell, for attack by other parts of the immune system, or can neutralize its target directly; for example, by blocking a part of a microbe that is essential for its invasion and survival. The production of antibodies is the main function of the humoral immune system.
Antibody Functions
Antibody functions include the following:
• Combine with viruses/toxins to prevent them from invading cells
• Attach to flagella of bacterium, restricting their movement
• Multi-bind to many bacteria at once, causing them to accumulate and prevent movement around the body
• Burst bacteria cell walls
• Attach to bacteria, making it easier for phagocytes to ingest them
Antibody Structure
Antibodies are heavy (~150 kDa) globular plasma proteins. They have sugar chains added to some of their amino acid residues; in other words, they are glycoproteins. Antibodies are typically made of the same basic structural units, each with two large heavy chains and two small light chains.
Heavy and light chains, variable and constant regions of an antibody
There are several different types of antibody heavy chains, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess. Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter.
The general structure of all antibodies is very similar. The Ig monomer is a Y-shaped molecule that consists of four polypeptide chains: two identical heavy chains, and two identical light chains connected by disulphide bonds. Each chain is composed of structural domains called immunoglobulin domains. These domains contain about 70-110 amino acids and are classified into different categories according to their size and function; for example, variable or IgV, and constant or IgC. The constant region determines the class of an immunoglobulin. All chains have a characteristic immunoglobulin fold in which two beta sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
However, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different tip structures, or antigen binding sites, to exist. This region is known as the hypervariable region. Each of these variants can bind to a different antigen. This enormous diversity of antibodies allows the immune system to recognize an equally wide variety of antigens. The large and diverse population of antibodies is generated by random combinations of a set of gene segments that encode different or paratopes, followed by random mutations in this area of the antibody gene, which create further diversity. The paratope is shaped at the amino terminal end of the antibody monomer by the variable domains from the heavy and light chains. The variable domain is also referred to as the FV region, and is the most important region for binding to antigens. More specifically, variable loops of β-strands, three each on the light (VL) and heavy (VH) chains are responsible for binding to the antigen.
Antibodies can occur in two physical forms, a soluble form that is secreted from the cell, and a membrane-bound form that is attached to the surface of a B cell and is referred to as the B cell receptor (BCR). The BCR is only found on the surface of B cells and facilitates the activation of these cells and their subsequent differentiation into either antibody factories called plasma cells, or memory B cells that will survive in the body and remember that same antigen so the B cells can respond faster upon future exposure. In most cases, interaction of the B cell with a T helper cell is necessary to produce full activation of the B cell and, therefore, antibody generation following antigen binding. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.07%3A_Antibodies/11.7A%3A_Antibody_Proteins_and_Antigen_Binding.txt |
Complex genetic mechanisms evolved which allow vertebrate B cells to generate a diverse pool of antibodies from relatively few antibody genes.
Learning Objectives
• Outline the two stages which result in antibody diversity: somatic (V(D)J) and recombination stages
Key Points
• Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies, a result of variation in amino acid composition that allows them to interact with many different antigens.
• Antibodies obtain their diversity through 2 processes. The first is called V(D)J (variable, diverse, and joining regions) recombination. During cell maturation, the B cell splices out the DNA of all but one of the genes from each region and combine the three remaining genes to form one VDJ segment.
• The second stage of recombination occurs after the B cell is activated by an antigen.In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation.
• As a consequence of these processes any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains.This serves to increase the diversity of the antibody pool and impacts the antibody’s antigen-binding affinity.
• Point mutations can result in the production of antibodies that have a lower or higher affinity with their antigen than the original antibody. B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities (called affinity maturation).
Key Terms
• Somatic hypermutation: a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (for example, microbes). A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism.
• V(D)J recombination: Also known as somatic recombination, this is a mechanism of genetic recombination in the early stages of immunoglobulin (Ig) and T cell receptors (TCR) production of the immune system.
Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies (glycoproteins belonging to the immunoglobulin superfamily). It is the variety in their amino acid composition that allows them to interact with many different antigens. It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen. Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited by the size of the human genome. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes.
Antibody Structure
Antibodies are typically made of basic structural units—each with two large heavy chains and two small light chains. There are several different types of antibody heavy chains, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess. Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter. Though the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different antigen binding sites to exist. This region is known as the hypervariable region. Each of these variants can bind to a different antigen. This enormous diversity of antibodies allows the immune system to recognize an equally wide variety of antigens.
Antibodies obtain their diversity through two processes:
V(D)J Recombination
The first stage is called somatic, or V(D)J, which stands for variable, diverse, and joining regions recombination. Several sets of genes are located within each of the three regions. During cell maturation, the B cell will splice out the DNA of all but one of the genes from each region and combine the three remaining genes together to form one VDJ segment. This segment, along with a constant region gene, forms the basis for subsequent antibody production.
It is estimated that given the number of variants in each of the three regions, approximately 10,000-20,000 unique antibodies are producible. V(D)J recombination takes place in the primary lymphoid tissue (bone marrow for B cells, and thymus for T cells ) and nearly randomly combines variable, diverse, and joining gene segments. It is due to this randomness in choosing different genes that it is able to diversely encode proteins to match antigens.
Somatic Hypermutation
The second stage of recombination occurs after the B cell is activated by an antigen. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it and is a major component of the process of affinity maturation. SHM diversifies B cell receptors used to recognize antigens and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. SHM results in approximately one nucleotide change per variable gene, per cell division. As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains. This serves to increase the diversity of the antibody pool and impacts the antibody’s antigen-binding affinity. Some point mutations will result in the production of antibodies that have a lower affinity with their antigen than the original antibody, and some mutations will generate antibodies with a higher affinity. B cells that express higher affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with lower affinity antibodies will not, and will die by apoptosis. Thus, B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities for function and survival. The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs after V(D)J recombination, and is dependent on help from helper T cells.
Antibody genes also re-organize in a process called class switching, which changes the base of the heavy chain to another. This creates a different isotype of the antibody while retaining the antigen specific variable region, thus allowing a single antibody to be used by several different parts of the immune system. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.07%3A_Antibodies/11.7B%3A_Antibody_Genes_and_Diversity.txt |
The clonal selection hypothesis is a widely accepted model for the immune system’s response to infection.
Learning Objectives
• Describe the clonal selection hypothesis in regards to the production of B cells
Key Points
• In 1954, immunologist Niels Jerne put forth the hypothesis that there is already a vast array of lymphocytes in the body before infection. The entrance of an antigen into the body results in the selection of only one type of lymphocyte to match it and produce a corresponding antibody to destroy it.
• B cells exist as clones derived from a particular cell. Thus the antibodies and their differentiated progenies can recognize and/or bind the same specific surface components composed of biological macromolecules of a given antigen. Clonality has important consequences for immunogenic memory.
• The clonal selection hypothesis states that an individual B cell expresses receptors specific to the distinct antigen, determined before the antibody ever encounters the antigen.
Key Terms
• clonal selection: An hypothesis which states that an individual lymphocyte (specifically, a B cell) expresses receptors specific to the distinct antigen, determined before the antibody ever encounters the antigen. Binding of Ag to a cell activates the cell, causing a proliferation of clone daughter cells.
• clone: A group of identical cells derived from a single cell.
The clonal selection hypothesis has become a widely accepted model for how the immune system responds to infection and how certain types of B and T lymphocytes are selected for destruction of specific antigens invading the body.
Four predictions of the clonal selection hypothesis
• Each lymphocyte bears a single type of receptor with a unique specificity (by V(D)J recombination).
• Receptor occupation is required for cell activation.
• The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical specificity as the parental cell.
• Those lymphocytes bearing receptors for self molecules will be deleted at an early stage.
In 1954, Danish immunologist Niels Jerne put forward a hypothesis which stated that there is already a vast array of lymphocytes in the body prior to any infection. The entrance of an antigen into the body results in the selection of only one type of lymphocyte to match it and produce a corresponding antibody to destroy the antigen. This selection of only one type of lymphocyte results in it being cloned or reproduced by the body extensively to ensure there are enough antibodies produced to inhibit and prevent infection. Australian immunologist Frank Macfarlane Burnet, with input from David W. Talmage, worked on this model and was the first to name it “clonal selection theory. ” Burnet explained immunological memory as the cloning of two types of lymphocyte. One clone acts immediately to combat infection whilst the other is longer lasting, remaining in the immune system for a long time, which results in immunity to that antigen. In 1958, Sir Gustav Nossal and Joshua Lederberg showed that one B cell always produces only one antibody, which was the first evidence for clonal selection theory.
B cells exist as clones. All B cells derive from a particular cell, and as such, the antibodies and their differentiated progenies can recognize and/or bind the same specific surface components composed of biological macromolecules ( epitope ) of a given antigen. Such clonality has important consequences, as immunogenic memory relies on it. The great diversity in immune response comes about due to the up to 109 clones with specificities for recognizing different antigens. Upon encountering its specific antigen, a single B cell, or a clone of cells with shared specificity, divides to produce many B cells. Most of such B cells differentiate into plasma cells that secrete antibodies into blood that bind the same epitope that elicited proliferation in the first place. A small minority survives as memory cells that can recognize only the same epitope. However, with each cycle, the number of surviving memory cells increases. The increase is accompanied by affinity maturation which induces the survival of B cells that bind to the particular antigen with high affinity. This subsequent amplification with improved specificity of immune response is known as secondary immune response. B cells that have not been activated by antigen are known as naive lymphocytes; those that have met their antigen, become activated, and have differentiated further into fully functional lymphocytes are known as effector B lymphocytes. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.07%3A_Antibodies/11.7C%3A_Clonal_Selection_of_Antibody-Producing_Cells.txt |
Isotype class switching is a biological mechanism that changes a B cell’s production of antibody from one class to another.
Learning Objectives
• Describe the process of class switch recombination that results in changes in the antibody-heavy chain
Key Points
• The antibody isotype of a B cell changes during cell development and activation. Immature B cells have never been exposed to an antigen and are known as naïve B cells. B cells begin to express both IgM and IgD when they reach maturity and renders the B cell ‘mature’ and ready to respond to antigen.
• If activated B cells encounter specific signaling molecules via their CD40 and cytokine receptors (both modulated by T helper cells), they undergo antibody class switching to produce IgG, IgA or IgE antibodies that have defined roles in the immune system.
• During class switch recombination the constant region portion of the antibody-heavy chain is changed, but the variable region of the heavy chain stays the same; thus, class switching does not affect antigen specificity.
• The antibody retains affinity for the same antigens, but can interact with different effector molecules. This allows different daughter cells from the same activated B cell to produce antibodies of different isotypes or subtypes (e.g. IgG1, IgG2 etc. ).
Key Terms
• isotype: Antibodies can come in different varieties known as isotypes, which refer to the genetic variations or differences in the constant regions of the heavy and light chains of the antibody.
• class switch recombination: A biological mechanism that changes a B cell’s production of antibody from one class to another; for example, from an isotype called IgM to an isotype called IgG.
Isotype Class Switching
Antibodies can come in different varieties, known as isotypes or classes. In placental mammals there are five antibody isotypes: IgA, IgD, IgE, IgG and IgM. They are each named with an “Ig” prefix that stands for immunoglobulin (another name for antibody) and differ in their biological properties, functional locations, and ability to deal with different antigens.
The antibody isotype of a B cell changes during cell development and activation. Immature B cells, which have never been exposed to an antigen, are known as naïve B cells and express only the IgM isotype in a cell surface bound form. B cells begin to express both IgM and IgD when they reach maturity; the co-expression of both of these immunoglobulin isotypes renders the B cell ‘mature’ and ready to respond to an antigen. B cell activation follows engagement of the cell-bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody-producing cell, called a plasma cell. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane-bound form. If these activated B cells encounter specific signaling molecules via their CD40 and cytokine receptors (both modulated by T helper cells), they undergo antibody class switching to produce IgG, IgA or IgE antibodies (from IgM or IgD) that have defined roles in the immune system.
Immunoglobulin class switching (or isotype switching, or isotypic commutation, or class switch recombination (CSR)) is a biological mechanism that changes a B cell’s production of antibody from one class to another; for example, from an isotype called IgM to an isotype called IgG. During this process, the constant region portion of the antibody-heavy chain is changed, but the variable region of the heavy chain stays the same (the terms “constant” and “variable” refer to changes or lack thereof between antibodies that target different epitopes). Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules. This allows different daughter cells from the same activated B cell to produce antibodies of different isotypes or subtypes (e.g. IgG1, IgG2 etc.).
Class switching occurs by a mechanism called class switch recombination (CSR) binding. Class switch recombination is a biological mechanism that allows the class of antibody produced by an activated B cell to change during a process known as isotype or class switching. During CSR, portions of the antibody-heavy chain locus are removed from the chromosome, and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a different isotype. Double-stranded breaks are generated in DNA at conserved nucleotide motifs, called switch (S) regions, which are upstream from gene segments that encode the constant regions of antibody-heavy chains; these occur adjacent to all heavy chain constant region genes with the exception of the δ-chain. DNA is nicked and broken at two selected S-regions by the activity of a series of enzymes, including Activation-Induced (Cytidine) Deaminase (AID), uracil DNA glycosylase and apyrimidic/apurinic (AP)-endonucleases. The intervening DNA between the S-regions is subsequently deleted from the chromosome, removing unwanted μ or δ heavy chain constant region exons and allowing substitution of a γ, α or ε constant region gene segment. The free ends of the DNA are rejoined by a process called non-homologous end joining (NHEJ) to link the variable domain exon to the desired downstream constant domain exon of the antibody-heavy chain. In the absence of non-homologous end joining, free ends of DNA may be rejoined by an alternative pathway biased toward microhomology joins. With the exception of the μ and δ genes, only one antibody class is expressed by a B cell at any point in time. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.07%3A_Antibodies/11.7D%3A_Isotype_Class_Switching.txt |
Memory B cells are a B cell sub-type that are formed following primary infection.
Learning Objectives
• Outline the process of memory B cell production
Key Points
• In the wake of the first (primary response) infection involving a particular antigen, the responding naïve cells (ones which have never been exposed to the antigen) proliferate to produce a colony of cells, most of which differentiate into the plasma cells, also called effector B cells.
• Effector B cells (which produce the antibodies ) clear away with the resolution of infection, and the rest persist as the memory cells that can survive for years, or even a lifetime.
• The antibody molecules present on a clone (a group of genetically identical cells) of B cells have a unique paratope. Some of the resulting paratopes (and the cells elaborating them) have a better affinity for the antigen and are more likely to proliferate than the others.
Key Terms
• paratope: That part of the molecule of an antibody that binds to an antigen
• memory cell: one of a number of types of white blood cells
Making Memory B Cells
Memory B cells are a B cell sub-type that are formed following a primary infection. In the wake of the first (primary response) infection involving a particular antigen, the responding naïve cells (ones which have never been exposed to the antigen) proliferate to produce a colony of cells. Most of them differentiate into the plasma cells, also called effector B cells (which produce the antibodies) and clear away with the resolution of infection. The rest persist as the memory cells that can survive for years, or even a lifetime.
To understand the events taking place, it is important to appreciate that the antibody molecules present on a clone (a group of genetically identical cells) of B cells have a unique paratope (the sequence of amino acids that binds to the epitope on an antigen).
Each time these cells are induced to proliferate due to an infection, the genetic region coding for the paratope undergoes spontaneous mutations with a frequency of about 1 in every 1600 cell divisions. This may not seem high, but because the cells divide so often, it ends up resulting in many mutations. The frequency of mutations in other cells is around 1 in 106, which is much lower.
All these events occur in the highly “eventful” germinal centers of lymphoid follicles, within the lymph nodes.
Some of the resulting paratopes (and the cells elaborating them) have a better affinity for the antigen (actually, the epitope) and are more likely to proliferate than the others.
Moreover, the number of different clones responding to the same antigen increases (polyclonal response) with each such exposure to the antigen and a greater number of memory cells persist. Thus, a stronger (basically, larger number of antibody molecules) and more specific antibody production is the hallmark of secondary antibody response.
The fact that all the cells of a single clone elaborate one (and only one) paratope, and that the memory cells survive for long periods, is what imparts a memory to the immune response. This is the principle behind vaccination and administration of booster.
The paratope is the part of an antibody which recognizes an antigen, the antigen-binding site of an antibody. It is a small region (15–22 amino acids) of the antibody’s Fv region and contains parts of the antibody’s heavy and light chains. The part of the antigen to which the paratope binds is called an epitope. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.07%3A_Antibodies/11.7E%3A_Making_Memory_B_Cells.txt |
The immune system protects organisms from infection first with the innate immune system, then with adaptive immunity.
Learning Objectives
• Generalize the role of the innate and adaptive immune system in regards to antibody response
Key Points
• When B cells and T cells are first activated by a pathogen, memory B-cells and T- cells develop.
• Throughout the lifetime of an animal these memory cells will “remember” each specific pathogen encountered, and are able to mount a strong response if the pathogen is detected again. This type of immunity is both active and adaptive.
• Active immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from the innate immune system.
Key Terms
• secondary response: the immune response occurring on second and subsequent exposures to an antigen, with a stronger response to a lesser amount of antigen, and a shorter lag time compared to the primary immune response
• primary response: the immune response occurring on the first exposure to an antigen, with specific antibodies appearing in the blood after a multiple day latent period
• adaptive immunity: the components of the immune system that adapt themselves to each new disease encountered and are able to generate pathogen-specific immunity.
The immune system is a system of biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, from viruses to parasitic worms, and distinguish them from the organism’s own healthy tissue. Pathogens can rapidly evolve and adapt to avoid detection and neutralization by the immune system. As a result, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess a rudimentary immune system, in the form of enzymes that protect against bacteriophage infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants and insects. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt over time to recognize specific pathogens more efficiently. Adaptive (or acquired) immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.
Disorders of the immune system can result in autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto’s thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system.
The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered. Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non- self molecules. In immunology, self molecules are those components of an organism’s body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.
When B cells and T cells are first activated by a pathogen, memory B-cells and T- cells develop. Throughout the lifetime of an animal these memory cells will “remember” each specific pathogen encountered, and are able to mount a strong response if the pathogen is detected again. This type of immunity is both active and adaptive because the body’s immune system prepares itself for future challenges. Active immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from the innate immune system. The innate system is present from birth and protects an individual from pathogens regardless of experiences, whereas adaptive immunity arises only after an infection or immunization and hence is “acquired” during life.
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The lymphatic system houses large populations of immune cells which are released upon detection of a pathogen.
Learning Objectives
• Describe the features of the lymphatic system as they relate to the immune response
Key Points
• The lymphatic system contains lymph: a fluid that bathes tissues and organs and contains white blood cells (not red blood cells).
• Once B and T cells mature, the majority of them enter the lymphatic system, where they are stored in lymph nodes until needed.
• Lymph nodes also store dendritic cells and macrophages; as antigens are filtered through the lymphatic system, these cells collect them so as to present them to B and T cells.
• The spleen, which is to blood what lymph nodes are to lymph, filters foreign substances and antibody -complexed pathogens from the blood.
Key Terms
• lymph: a colorless, watery, bodily fluid carried by the lymphatic system, consisting mainly of white blood cells
Lymphatic system
Lymph, the watery fluid that bathes tissues and organs, contains protective white blood cells, but does not contain erythrocytes (red blood cells). Lymph moves about the body through the lymphatic system, which is made up of vessels, lymph ducts, lymph glands, and organs such as tonsils, adenoids, thymus, and spleen. Although the immune system is characterized by circulating cells throughout the body, the regulation, maturation, and intercommunication of immune factors occur at specific sites that are known as lymph nodes.
The blood circulates immune cells, proteins, and other factors through the body. Approximately 0.1 percent of all cells in the blood are leukocytes, which include monocytes (the precursor of macrophages) and lymphocytes. Most cells in the blood are red blood cells. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by a process called extravasation (passing through to surrounding tissue).
Recall that cells of the immune system originate from stem cells in the bone marrow. B cell maturation occurs in the bone marrow, whereas progenitor cells migrate from the bone marrow and develop and mature into naïve T cells in the organ called the thymus. On maturation, T and B lymphocytes circulate to various destinations. Lymph nodes scattered throughout the body house large populations of T and B cells, dendritic cells, and macrophages. Lymph gathers antigens as it drains from tissues. These antigens are filtered through lymph nodes before the lymph is returned to circulation. Antigen-presenting cells (APCs) in the lymph nodes capture and process antigens, informing nearby lymphocytes about potential pathogens.
The spleen houses B and T cells, macrophages, dendritic cells, and NK cells. The spleen is also the site where APCs that have trapped foreign particles in the blood can communicate with lymphocytes. Antibodies are synthesized and secreted by activated plasma cells in the spleen, which filters foreign substances and antibody-complexed pathogens from the blood. Functionally, the spleen is to the blood as lymph nodes are to the lymph.
11.8B: Classes of T Cells
T cells play a central role in cell-mediated immune response through the use of the surface T cell receptor to recognize peptide antigens.
Learning Objectives
• Distinguish between: naive, effector (helper and cytotoxic), memory and regulatory T cells
Key Points
• T cell progenitors are derived from the bone marrow but travel to the thymus where they mature.
• T cells can be divided into three main subtypes: effector, memory, and regulatory cells. Each type performs a distinct function during an immune response to foreign antigens.
• T cells subtypes are differentiated by the expression of unique cell surface markers, such as CD4 for helper T cells and CD8 for cytolytic or cytotoxic T cells.
Key Terms
• cytotoxic: of, relating to, or being a cytotoxin
• cytolytic: Of or pertaining to cytolysis
Cellular immunity is mediated by T lymphocytes, also called T cells. Their name refers to the organ from which they’re produced: the thymus. This type of immunity promotes the destruction of microbes residing in phagocytes, or the killing of infected cells to eliminate reservoirs of infection. T cells do not produce antibody molecules. They have antigen receptors that are structurally related to antibodies. These structures help recognize antigens only in the form of peptides displayed on the surface of antigen-presenting cells.
T cells consist of functionally distinct populations. These include naive T cells that recognize antigens and are activated in peripheral lymphoid organs. This activation results in the expansion of the antigen-specific lymphocyte pool and the differentiation of these cells into effector and memory cells. Effector cells include helper T cells, and cytolytic or cytotoxic T cells. In response to antigenic stimulation, helper T cells (characterized by the expression of CD4 marker on their surface) secrete proteins called cytokines, whose function is to stimulate the proliferation and differentiation of the T cells themselves, as well as other cells, including B cells, macrophages, and other leukocytes. Cytolytic or cytotoxic T cells (characterized by the expression of CD8 marker on their surface) kill cells that produce foreign antigens, such as cells infected by viruses and other intracellular microbes.
Memory T cells are an expanded population of T cells specific for antigens that can respond rapidly to subsequent encounter with that antigen and differentiate into effector cell to eliminate the antigen. Another class of T cells called regulatory T cells function to inhibit immune response and resolve inflammation. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.08%3A_T_Cells_and_Cellular_Immunity/11.8A%3A_Cytotoxic_T_Lymphocytes_and_Mucosal_Surfaces.txt |
Cell-mediated immunity involves cytotoxic T cells recognizing infected cells and bringing about their destruction.
Learning Objectives
• Summarize the cell-mediated immune response
Key Points
• Once a pathogen enters a cell, it can no longer be detected by the humoral immune response; instead, the cell-mediated immune response must take over to kill the infected cell before it can allow the virus or bacteria to replicate and spread.
• T cells recognize infected cells by interacting with antigen present on their MHC II molecules; before a T cell can do so, it must be activated via interaction with an antigen presenting cell, or APC.
• Once a cytotoxic T cell (TC) is activated, it will clone itself, producing many TC cells with the correct receptors; some portion of the cells are active and will help destroy infected cells, while others are inactive memory cells that will create more active TC cells if the infection returns.
• Helper T cells (TH cells) also aid in cell-mediated immunity by releasing signaling molecules known as cytokines which can recruit natural killer cells and phagocytes to destroy infected cells and further activate TC cells; they do not directly destroy pathogens.
Key Terms
• cytotoxic T cell: a subgroup of lymphocytes (white blood cells) that are capable of inducing death to infected somatic or tumor cells; part of cell-mediated immunity
• cytokine: any of various small regulatory proteins that regulate the cells of the immune system; they are released upon binding of PRRs to PAMPS
T cells
Just as the humoral immune response has B cells which mediate its response, the cellular immune response has T cells, which recognize infected cells and destroy them before the pathogen inside can replicate and spread to infect other cells. Unlike B cells, T lymphocytes (T cells) are unable to recognize pathogens without assistance. First, an antigen-presenting cell (APC, such as a dendritic cell or a macrophage ) detects, engulfs (via phagocytosis in the case of macrophages or by entry of the pathogen of its own accord in the case of dendritic cells), and digests pathogens into hundreds or thousands of antigen fragments. These fragments are then transported to the surface of the APC, where they are presented on proteins known as Major Histocompatibility Complexes class II (MHC II, see ). T cells become activated towards a certain antigen once they encounter it displayed on an MHC II. After a virus or bacteria enters a cell, it can no longer be detected by the humoral immune response. Instead, the cellular immune response must take over. To do so, a T cell will become activated by interacting with an antigen of the infecting cell or virus presented on the MHC II of an APC.
Cytotoxic T cells mediate one arm of the cellular immune response
There are two main types of T cells: helper T lymphocytes (TH) and the cytotoxic T lymphocytes (TC). The TH lymphocytes function indirectly to tell other immune cells about potential pathogens, while cytotoxic T cells (TC) are the key component of the cell-mediated part of the adaptive immune system which attacks and destroys infected cells. TCcells are particularly important in protecting against viral infections because viruses replicate within cells where they are shielded from extracellular contact with circulating antibodies. Once activated, the TCcreates a large clone of cells with one specific set of cell-surface receptors, similar to the proliferation of activated B cells. As with B cells, the clone includes active TC cells and inactive memory TC cells. The resulting active TC cells then identify infected host cells.
TC cells attempt to identify and destroy infected cells by triggering apoptosis (programmed cell death) before the pathogen can replicate and escape, thereby halting the progression of intracellular infections. To recognize which cells to pursue, TC recognize antigens presented on MHC I complexes, which are present on all nucleated cells. MHC I complexes display a current readout of intracellular proteins inside a cell and will present pathogen antigens if the pathogen is present in the cell. TC cells also support NK lymphocytes to destroy early cancers.
Cytokines released by TH cells recruit NK cells and phagocytes
Cytokines are signaling molecules secreted by a TH cell in response to a pathogen-infected cell; they stimulate natural killer cells and phagocytes such as macrophages. Phagocytes will then engulf infected cells and destroy them. Cytokines are also involved in stimulating TC cells, enhancing their ability to identify and destroy infected cells and tumors. A summary of how the humoral and cell-mediated immune responses are activated appears in. B plasma cells and TC cells are collectively called effector cells because they are involved in “effecting” (bringing about) the immune response of killing pathogens and infected host cells.
11.8D: Regulatory T Cells
Regulatory T cells are a subset of T cells which modulate the immune system and keep immune reactions in check.
Learning Objectives
• Describe the function and types of regulatory T cells
Key Points
• Regulatory T cells (Tregs) are critical to the maintenance of immune cell homeostasis as evidenced by the consequences of genetic or physical ablation of the Treg population.
• Tregs are classified into natural or induced Tregs; natural Tregs are CD4+CD25+ T-cells which develop, and emigrate from the thymus to perform their key role in immune homeostasis.
• Adaptive Tregs are non-regulatory CD4+ T-cells which acquire CD25 (IL-2R alpha) expression outside of the thymus and are typically induced by inflammation and disease processes, such as autoimmunity and cancer.
Key Terms
• autoimmunity: The condition where one’s immune system attacks one’s own tissues, i.e., an autoimmune disorder.
Regulatory T cells are a component of the immune system that suppress immune responses of other cells. This is an important “self-check” built into the immune system to prevent excessive reactions and chronic inflammation. Regulatory T cells come in many forms, with the most well-understood being those that express CD4, CD25, and Foxp3. These cells are also called CD4+CD25+ regulatory T cells, or Tregs. These cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity.
CD4+Foxp3+ regulatory T cells have been called “naturally-occurring” regulatory T cells, to distinguish them from “suppressor” T cell populations that are generated in vitro. Additional suppressor T cell populations include Tr1, Th3, CD8+CD28, and Qa-1 restricted T cells. The contribution of these populations to self- tolerance and immune homeostasis is less well defined. FOXP3 can be used as a good marker for CD4+CD25+ T cells as well as recent studies showing evidence for FOXP3 in CD4+CD25- T cells.
An additional regulatory T cell subset, induced regulatory T cells, are also needed for tolerance and suppression. Induced Regulatory T (iTreg) cells (CD4+CD25+Foxp3+) are suppressive cells involved in tolerance. iTreg cells have been shown to suppress T cell proliferation and experimental autoimmune diseases. iTreg cells develop from mature CD4+ conventional T cells outside of the thymus: a defining distinction between natural regulatory T (nTreg) cells and iTreg cells. Though iTreg and nTreg cells share a similar function iTreg cells have recently been shown to be an essential non-redundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses. Acute depletion of the iTreg cell pool in mouse models has resulted in inflammation and weight loss. The contribution of nTreg cells versus iTreg cells in maintaining tolerance is unknown, but both are important. Epigenetic differences have been observed between nTreg and iTreg cells, with the former having more stable Foxp3 expression and wider demethylation. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.08%3A_T_Cells_and_Cellular_Immunity/11.8C%3A_Cell-Mediated_Immunity.txt |
Learning Objectives
• Discuss the role of the T cell receptor (TCR)
T lymphocytes have a dual specificity: they recognize polymorphic residues of self major histocompatibility complex (MHC) molecules, which accounts for their MHC restriction; they also recognize residues of peptide antigens displayed by these MHC molecules, which is responsible for their specificity. MHC molecules and peptides form complexes on the surface of antigen presenting cells (APCs). The receptor that recognizes these peptide-MHC complexes is called the T Cell Receptor (TCR). Clones of T cells with different specificities express different TCRs.
The biochemical signals that are triggered in T cells following antigen recognition are transduced not by the TCR itself, but by invariant proteins (CD3, and zeta), which are non-covalently linked to the antigen receptor to form the TCR complex. T cells also express other membrane receptors that do not recognize antigens but participate in responses to antigens; these are collectively called ‘accessory molecules’. The physiologic role of some accessory molecules is to deliver signals to the T cells that function in concert with signals from the TCR complex to fully activate the cell.
The antigen receptor of MHC-restricted CD4 helper T cells and CD8 cytolytic T cell is a heterodimer consisting of two transmembrane polypeptide chains, designated alpha and beta, covalently linked to each other by disulfide bonds. Each alpha and beta chain consists of one variable domain (V), one constant domain (C), a hydrophobic transmembrane region, and a short cytoplasmic region. The V regions of the TCR contain short stretches of amino acids where the variability between different TCRs is concentrated, and these form the hypervariable or complementarity-determining regions (CDRs). The recognition of peptide-MHC complexes is mediated by CDRs formed by both the alpha and beta chains of the TCR.
Key Points
• Many TCRs recognize the same antigen and many antigens are recognized by the same TCR.
• The TCR is composed of two different protein chains (that is, it is a heterodimer). In 95% of T cells, this consists of an alpha (α) and beta (β) chain, whereas in 5% of T cells this consists of gamma and delta (γ/δ) chains.
• When the TCR engages with antigen and MHC, the T lymphocyte is activated through a series of biochemical events mediated by associated enzymes, co- receptors, specialized accessory molecules, and activated or released transcription factors.
Key Terms
• polymorphic: relating to polymorphism (any sense), able to have several shapes or forms
• major histocompatibility complex: MHC is a cell surface molecule that mediate interactions of immune cells with other leukocytes or body cells. MHC determines compatibility of donors for organ transplants as well as one’s susceptibility to an autoimmune disease. In humans, MHC is also called human leukocyte antigen (HLA).
11.8F: Adaptive Immunity and the Immunoglobulin Superfamily
Learning Objectives
• Describe the role of immunoglobulins in the adaptive immune response, specifically in humoral immunity
Adaptive immunity is stimulated by exposure to infectious agents and increases in magnitude and defensive capabilities with each successive exposure to a particular microbe. The defining characteristics of adaptive immunity are specificity for distinct molecules and an ability to “remember” and respond more vigorously to repeated exposures to the same microbe.
The components of adaptive immunity are lymphocytes and their products. There are two types of adaptive immune responses: humoral immunity and cell-mediated immunity. These are driven by different elements of the immune system and function to eliminate different types of microbes. Protective immunity against a microbe may be induced by the host ‘s response to the microbe or by the transfer of antibodies or lymphocytes specific for the microbe. Antibodies or Immunoglobulins bind antigens in the recognition phase and the effector phase of humoral immunity.
The Immunoglobulin Superfamily
Immunoglobulins are produced in a membrane -bound form by B lymphocytes. These membrane molecules function as B cell receptors for antigens. The interaction of antigens with membrane antibodies on naive B cells initiates B cell activation. These activated B cells produce a soluble form of immunoglobulin that triggers effector mechanisms to eliminate antigens.
These antibodies are part of a larger family called the immunoglobulin superfamily. The immunoglobulin superfamily (IgSF) is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on structural features shared with immunoglobulins, which are also known as antibodies. They all possess a domain known as an immunoglobulin domain or fold. Members of the IgSF include cell surface antigen receptors, co-receptors, and co-stimulatory molecules of the immune system, molecules involved in antigen presentation to lymphocytes, cell adhesion molecules, certain cytokine receptors, and intracellular muscle proteins. They are commonly associated with roles in the immune system.
Key Points
• The concept of adaptive immunity suggests de novo generation in each individual of extremely large repertoires of diversified receptors and selective expansion of receptors that match the antigen /pathogen.
• Adaptive immune receptors of T and B lymphoid cells belong to the immunoglobulin superfamily and are created by rearrangement of gene segments.
• Immunoglobulins are glycoproteins in the immunoglobulin superfamily that function as antibodies.
Key Terms
• cytokine: Any of various small regulatory proteins that regulate the cells of the immune system.
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Dendritic cells are immune cells that function to process antigens and present them to T cells.
Learning Objectives
• Discuss the mechanism of action for dendritic cells
Key Points
• Dendritic cells function as antigen presenting cells.
• Dendritic cells are present in small quantities in tissues that are in contact with the external environment, mainly the skin (where there is a specialized dendritic cell type called Langerhans cells) and the inner lining of the nose, lungs, stomach and intestines.
• Once activated, dendritic cells migrate to the lymphoid tissues where they interact with T cells and B cells to initiate and shape the adaptive immune response.
Key Terms
• lymphoid organs: lymph nodes, spleen, and gut-associated lymphoid tissue where lymphocytes reside.
Dendritic cells are present in lymphoid organs, the epithelia of the skin, the gastrointestinal and respiratory tracts, and in most parenchymal organs. These cells are identified morphologically by their membranous projections that resemble spines. All dendritic cells are thought to arise from bone marrow precursors. Most, called myeloid dendritic cells, are related in lineage to mononuclear phagocytes. Immature dendritic cells (e.g. Langerhans cells of the epidermis) are located in main portals of entry of microbes (skin and gut epithelia). The function of epithelial dendritic cells is to capture microbial protein antigens and to transport the antigens to draining lymph nodes. During their migration to the lymph nodes, the dendritic cells mature to become extremely efficient at presenting antigens and stimulating naive T cells, hence their classification as antigen presenting cells. Mature dendritic cells reside in the T cell zones of the lymph nodes, and in this location they display antigens to T cells. Subsets of dendritic cells can be distinguished by the expression of cell surface markers. Different subpopulations of dendritic cells may stimulate distinct types of T cell effector responses. Some may even inhibit T cell activation.
Dendritic cells are constantly in communication with other cells in the body. This communication can take the form of direct cell-to-cell contact based on the interaction of cell-surface proteins. An example of this includes the interaction of the membrane proteins of the B7 family of the dendritic cell with a CD28 cell surface molecule present on the lymphocyte. However, the cell-cell interaction can also take place at a distance via soluble factors such as cytokines. For example, stimulating dendritic cells in vivo with microbial extracts causes the dendritic cells to rapidly begin producing interleukin 12 (IL-12). IL-12 is a signal that helps differentiate naive CD4 T cells into a helper T cell phenotype. The ultimate consequence is priming and activation of the immune system for attack against the antigens which the dendritic cell presents on its surface.
11.9B: Macrophages
Phagocytosis is a front-line defense against pathogen attack requiring the concerted action of macrophages.
Learning Objectives
• Describe the role of macrophages in the immune system
Key Points
• Macrophages are cells produced by the differentiation of monocytes in tissues.
• They are specialized phagocytic cells that attack foreign substances and infectious microbes through destruction and ingestion.
• Macrophages can be identified by specific expression of a number of proteins measured by flow cytometry or immunohistochemistry.
Key Terms
• phagocyte: A cell of the immune system, such as a neutrophil, macrophage or dendritic cell, that engulfs and destroys viruses, bacteria and waste materials, or in the case of mature dendritic cells; displays antigens from invading pathogens to cells of the lymphoid lineage.
• interferon-gamma: a cytokine that is critical for innate and adaptive immunity against viral and intracellular bacterial infections.
Macrophages are antigen presenting cells that actively phagocytose large particles. Therefore, they play an important role in presenting antigens derived from phagocytosed infectious organisms such as bacteria and parasites. In the effector phase of cell-mediated immunity, differentiated effector T cells recognize microbial antigens on phagocytes and activate the macrophages to destroy these engulfed microbes. Most macrophages express high levels of interferon-gamma, a mechanism through which antigen presentation and T cell activation is enhanced. Macrophages can be identified by specific expression of a number of proteins including CD14, CD40, CD11b, F4/80(mice)/EMR1(human), lysozyme M, MAC-1/MAC-3 and CD68. They move by the action of amoeboid movement.
Macrophages are not cells exclusive to the immune system; they also play a central function in many other aspects of embryonic development, homeostasis and wound repair. Resident macrophages become adapted to perform particular functions in different organs; so that brain macrophages (microglia) are very different from alveolar macrophages of the lung, Kupffer cells of the liver, or the largest tissue macrophage population, those lining the wall of the gut.
Monocytes are recruited into tissues in response to a very wide range of different stimuli. Where a pathogen is involved, they are commonly preceded by neutrophils, which release a range of toxic agents designed to kill extracellular pathogens. The macrophage then has the task of clearing both the dead pathogens and the dead neutrophils. To enter a tissue, the monocyte in peripheral blood must adhere to the vessel wall, cross the endothelial cell barrier, and then migrate towards the stimulus; a process known as chemotaxis.
The process of recruitment of neutrophils and macrophages involves the resident macrophages which act as sentinels. They respond to local stimuli by producing cytokines that make the endothelial cells more sticky (through the increased expression of cell adhesion molecules such as P-selectin) and so-called chemokines, that promote the directed migration of inflammatory cells. Monocytes may also migrate towards increasing concentrations of molecules produced by microorganisms themselves, by damaged tissues, or by the activation of the complement or clotting cascades which release bioactive peptides such as C5a.
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Clonal selection and tolerance select for survival of lymphocytes that will protect the host from foreign antigens.
Learning Objectives
• Describe the importance of central and peripheral tolerance and distinguish between positive and negative clonal selection
Key Points
• Clonal selection occurs after immature lymphocytes express antigen receptors.
• Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self.
• Both developing B cells and T cells are subject to negative selection during a short period after antigen receptors are expressed.
• If, during embryonic development, it encounters its programmed antigen as part of a normal host substance (self), the lymphocyte is somehow destroyed or inactivated. This mechanism removes lymphocytes that can destroy host tissues and thereby creates tolerance for self.
Key Terms
• lymphocyte: A type of white blood cell or leukocyte that is divided into two principal groups and a null group: B-lymphocytes, which produce antibodies in the humoral immune response, T-lymphocytes, which participate in the cell-mediated immune response, and the null group, which contains natural killer cells, cytotoxic cells that participate in the innate immune response.
• antigens: In immunology, an antigen is a substance that evokes the production of one or more antibodies.
• T cells: A lymphocyte, from the thymus, that can recognise specific antigens and can activate or deactivate other immune cells.
Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. The concept of central tolerance was proposed in 1959 as part of a general theory of immunity and tolerance. It was hypothesized that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive. The theory that self-tolerance is ‘learned’ during lymphocyte development was a major conceptual contribution to immunology. It was experimentally substantiated in the late 1980’s when tools to analyze lymphocyte development became available. Central tolerance is distinct from periphery tolerance in that it occurs while cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery. Peripheral tolerance is generated after the cells reach the periphery. Regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self (or foreign)-reactive T cells in the thymus during T cell differentiation. However, they exert their immune suppression in the periphery on other self (or foreign)-reactive T cells.
Clonal selection occurs after immature lymphocytes express antigen receptors. The cells with useful receptors are preserved, and many potentially harmful, self antigen-reactive cells are eliminated by processes of selection induced by antigen receptor engagement. The preservation of useful specificities is called positive selection. Positive selection ensures maturation of T cells whose receptors bind weakly to self major histocompatibility complex molecules. Negative selection is the process that eliminates developing lymphocytes whose antigen receptors bind strongly to self antigens present in the lymphoid organs. Both developing B cells and T cells are subject to negative selection during a short period after antigen receptors are expressed. Negative selection of developing lymphocytes is an important mechanism for maintaining central tolerance. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.10%3A_Immunity_and_Molecular_Signals/11.10A%3A_Clonal_Selection_and_Tolerance.txt |
Cytokines and chemokines are both small proteins secreted by cells of the immune system.
Learning Objectives
• Summarize the role of cytokines and chemokines
Key Points
• Cytokines and chemokines are important in the production and growth of lymphocytes, and in regulating responses to infection or injury, such as inflammation and wound healing.
• Cytokines are the general category of messenger molecules, while chemokines are a special type of cytokine that directs the migration of white blood cells to infected or damaged tissues.
• A cytokine and a chemokine both use chemical signals to induce changes in other cells, but the latter are specialized to cause cell movement.
Key Terms
• cytokine: Any of various small regulatory proteins that regulate the cells of the immune system.
• chemokine: Any of various cytokines, produced during inflammation, that organize the leukocytes.
• chemotaxis: The movement of a cell or an organism in response to a chemical stimulant.
CYTOKINES
These are small cell-signaling protein molecules that are secreted by numerous cells, and are a category of signaling molecules used extensively in intercellular communication.
Cytokines can be classified as proteins, peptides, or glycoproteins. The term “cytokine” encompasses a large and diverse family of regulators produced throughout the body by cells of diverse embryological origin. The term has also been used to refer to the immunomodulating agents, such as interleukins and interferons.
Biochemists disagree as to which molecules should be termed cytokines and which hormones. As we learn more about each, anatomic and structural distinctions between the two are fading. Classic protein hormones circulate in nanomolar (10-9) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10-12) concentrations that can increase up to 1,000-fold during trauma or infection.
The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the interface with the external environment), are potent producers of IL-1, IL-6, and TNF-alpha. In contrast, classic hormones, such as insulin, are secreted from discrete glands (e.g., the pancreas).
As of 2008, the current terminology refers to cytokines as immunomodulating agents.
CHEMOKINES
These are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.
Proteins are classified as chemokines according to shared structural characteristics, such as small size (they are all approximately 8-10 kilodaltons in size), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape. However, these proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines.
Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development.
Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been described for other invertebrates. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.
11.10C: Superantigens
Superantigens are a class of antigens that cause activation of T-cells and massive cytokine release.
Learning Objectives
• Describe the mechanism of action for superantigens and the effects
Key Points
• Superantigens (SAgs) are microbial products that have the ability to promote massive activation of immune cells, leading to the release of inflammatory mediators that can ultimately result in hypotension, shock, organ failure, and death.
• They achieve this by simultaneously binding and activating major histocompatibility complex class II molecules on antigen -presenting cells and T-cell receptors on T lymphocytes bearing susceptible Vβ regions.
• The resulting Th1 response may divert the immune system from effective microbial clearance and/or result in the cytokine -mediated suppression and deletion of activated T cells.
Key Terms
• interferon: Any of a group of glycoproteins, produced by the immune system, that prevent viral replication in infected cells.
• Kawasaki disease: A disease in which the medium-sized blood vessels throughout the body become inflamed. Symptoms include fever, lymphadenopathy, and elevated platelet count.
• superantigen: an antigen, which has a powerful interaction with T-lymphocytes
Superantigens (SAgs) are proteins that cause the T-cells of the immune system to over-react to infection. They are produced by certain infectious bacteria and viruses. The immune system over-reaction to the antigen causes a group of diseases that manifest in fever and shock, such as food poisoning, toxic shock syndrome, and Kawasaki disease. Common bacterial species that may use a superantigen as part of their virulence strategy are staphylococci and streptococci.
These bacteria usually live harmlessly on the body, but can cause infections in certain circumstances. The superantigens of each species are, like antigens, molecules the immune system recognizes as being foreign. Superantigens cause symptoms of illness by tricking the T-cells of the immune system into over-reacting to these molecules. Parts of a bacterium or a virus are usually recognized by the macrophage cells of the immune system. The macrophage ingests the foreign invaders and breaks them down. Then the macrophage takes parts of the broken-down invader or other molecules that it ingested and posts the fragments on the outside of the cell using a major histocompatibility complex (MHC) to hold the fragment.
The large number of activated T-cells generates a massive immune response which is not specific to any particular epitope on the SAg. This undermines one of the fundamental strengths of the adaptive immune system, that is, its ability to target antigens with high specificity. More importantly, the large number of activated T-cells secretes large amounts of cytokines, the most important of which is Interferon gamma. This excess amount of IFN-gamma is in turn what activates the macrophages. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.10%3A_Immunity_and_Molecular_Signals/11.10B%3A_Cytokines_and_Chemokines.txt |
The complement system helps antibodies and phagocytic cells clear pathogens from an organism.
Learning Objectives
• Describe the function of the complement system
Key Points
• The complement system has originally been identified as the part of the immune system called the innate immune system.
• The complement system can also be recruited and brought into action by the adaptive immune system.
• The three biochemical pathways that activate the complement system are the classical complement pathway, the alternative complement pathway, and the lectin pathway.
• The complement system consists of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors. When stimulated by a trigger, proteases in the system cleave specific proteins to release cytokines that amplify further cleavages.
• The end-result of this activation cascade is the massive amplification of the response and activation of the cell-killing membrane attack complex.
Key Terms
• opsonization: the process of an antigen bound by antibody or complement to attract phagocytic cells.
The Complement System
The serum complement system, which represents a chief component of innate immunity, not only participates in inflammation but also acts to enhance the adaptive immune response. Specific activation of the complement via innate recognition proteins or secreted antibody releases cleavage products that interact with a wide range of cell surface receptors found on myeloid, lymphoid, and stromal cells. This intricate interaction among complement activation products and cell surface receptors provides a basis for the regulation of both B and T cell responses.
The complement system plays a crucial role in the innate defense against common pathogens. Activation of the complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of the complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now understood that the complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges.
Activation of the Complement System
The complement system can be activated through three major pathways: classical, lectin, and alternative. Initiation of the classical pathway occurs when C1q, in complex with C1r and C1s serine proteases (the C1 complex), binds to the Fc region of complement-fixing antibodies (generally IgG1and IgM) attached to pathogenic surfaces. Autocatalytic activation of C1r and C1s in turn cleaves C4 and C2 into larger (C4b, C2a) and smaller (C4a, C2b) fragments. The larger fragments associate to form C4bC2a on pathogenic surfaces, and the complex gains the ability to cleave C3 and is termed the C3 convertase.
Generation of the C3 convertase, which cleaves C3 into the anaphylatoxin C3a and the opsonin C3b, is the point at which all complement activation cascades converge. When C3 is cleaved into C3b, it exposes an internal thioester bond that allows stable covalent binding of C3b to hydroxyl groups on proximate carbohydrates and proteins. This activity underpins the entire complement system by effectively “tagging” microorganisms as foreign, leading to further complement activation on and around the opsonized surface and terminating in the production of anaphylatoxins and assembly of membrane attack complexes.
Functions of the Complement System
The functions of the complement system, oposonization, lysis, and generation of the inflammatory response through soluble mediators, are paradigmatic and represent a well-characterized component of an innate host defense. It has become increasingly understood that complement functions in host defense extend beyond innate immune responses. The finding that B lymphocytes bound C3 raised the question as early as in the 1970s as to whether the complement system was involved in adaptive immune responses. Subsequent work demonstrated that depletion of C3 impaired humoral immune responses and provided direct evidence that efficient adaptive responses were contingent on an intact complement system in some cases.
Further study in animals bearing natural complement deficiencies implicated the classical pathway as a crucial mechanism for efficient antigen trapping and retention in lymphoid tissues (e.g., splenic follicles), suggesting that a major function of the complement system was to localize foreign antigens into immune sites important for lymphocytes responses.
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Learning Objectives
• Explain MHC polymorphism
Major histocompatibility complex (MHC) is a cell-surface molecule encoded by a large gene family in all vertebrates. MHC molecules display a molecular fraction called an epitope and mediate interactions of leukocytes with other leukocytes or body cells. The MHC gene family is divided into three subgroups—class I, class II, and class III. Diversity of antigen presentation, mediated by MHC classes I and II, is attained in multiple ways:
1. The MHC’s genetic encoding is polygenic,
2. MHC genes are highly polymorphic and have many variants,
3. Several MHC genes are expressed from both inherited alleles (variants).
MHC gene families are found in all vertebrates, though they vary widely. Chickens have among the smallest known MHC regions (19 genes).
In humans, the MHC region occurs on chromosome 6. Human MHC class I and II are also called human leukocyte antigen (HLA). To clarify the usage, some of the biomedical literature uses HLA to refer specifically to the HLA protein molecules and reserves MHC for the region of the genome that encodes for this molecule, but this is not a consistent convention.
The most intensely-studied HLA genes are the nine so-called classical MHC genes: HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. In humans, the MHC is divided into three regions: classes I, II, and III. The A, B, C, E, F, and G genes belong to MHC class I, whereas the six D genes belong to class II. MHC genes are expressed in co-dominant fashion. This means that the alleles inherited from both progenitors are expressed in an equivalent way. As there are 3 Class-I genes, named in humans HLA-A, HLA-B and HLA-C, and as each person inherits a set of genes from each progenitor, that means that any cell in an individual can express 6 different types of MHC-I molecules.
In the Class-II locus, each person inherits a couple of genes HLA-DP (DPA1 and DPA2, which encode α and β chains), a couple of genes HLA-DQ (DQA1 and DQA2, for α and β chains), one gene HLA-DRα (DRA1) and one or two genes HLA-DRβ (DRB1 and DRB3, -4 o -5). That means that one heterozygous individual can inherit 6 or 8 Class-II alleles, three or four from each progenitor.
The set of alleles that is present in each chromosome is called MHC haplotype. In humans, each HLA allele is named with a number. Each heterozygous individual will have two MHC haplotypes, one in each chromosome (one of paternal origin and the other of maternal origin).
The MHC genes are highly polymorphic; this means that there are many different alleles in the different individuals inside a population. The polymorphism is so high that in a mixed population (non-endogamic) there are not two individuals with exactly the same set of MHC genes and molecules, with the exception of identical twins.
The polymorphic regions in each allele are located in the region for peptide contact, which is going to be displayed to the lymphocyte. For this reason, the contact region for each allele of MHC molecule is highly variable, as the polymorphic residues of the MHC will create specific clefts in which only certain types of residues of the peptide can enter. This imposes a very specific link between the MHC molecule and the peptide, and it implies that each MHC variant will be able to bind specifically only those peptides that are able to properly enter in the cleft of the MHC molecule, which is variable for each allele. In this way, the MHC molecules have a broad specificity, because they can bind many, but not all, types of possible peptides.
The evolution of the MHC polymorphism ensures that a population will not succumb to a new pathogen or a mutated one, because at least some individuals will be able to develop an adequate immune response to win over the pathogen. The variations in the MHC molecules (responsible for the polymorphism) are the result of the inheritance of different MHC molecules, and they are not induced by recombination, as it is the case for the antigen receptors.
Because of the high levels of allelic diversity found within its genes, MHC has also attracted the attention of many evolutionary biologists.
Key Points
• Diversity of antigen presentation, mediated by MHC classes I and II, is attained in three ways: (1) the MHC’s genetic encoding is polygenic, (2) MHC genes are highly polymorphic and have many variants, (3) several MHC genes are expressed from both inherited alleles.
• Human MHC class I and II are also called human leukocyte antigen (HLA).
• The MHC genes are highly polymorphic; this means that there are many different alleles in the different individuals inside a population.
• The evolution of the MHC polymorphism ensures that a population will not succumb to a new pathogen or a mutated one, because at least some individuals will be able to develop an adequate immune response to win over the pathogen.
Key Terms
• allele: One of a number of alternative forms of the same gene occupying a given position on a chromosome.
• epitope: That part of a biomolecule (such as a protein) that is the target of an immune response.
• polygenic: Having an infinite number of derivatives at a point (otherwise it is monogenic).
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Naturally acquired active immunity occurs when a person is exposed to a live pathogen, develops the disease, and then develops immunity.
Learning Objectives
• Compare and contrast: active natural and active artifical immunity
Key Points
• Once a microbe penetrates the body’s skin, mucous membranes, or other primary defenses, it interacts with the immune system.
• Active immunization entails the introduction of a foreign molecule into the body, which causes the development of an immnune response via activation of the T cells and B cells.
• The principle behind immunization is to introduce an antigen, derived from a disease-causing organism, that stimulates the immune system to develop protective immunity against that organism, but which does not itself cause the pathogenic effects of that organism.
Key Terms
• immunity: the state of being insusceptible to a specific thing.
• vaccination: inoculation with a vaccine in order to protect a particular disease or strain of disease.
Immunity is the state of protection against infectious disease conferred either through an immune response generated by immunization or previous infection, or by other non-immunological factors. There are two ways to acquire active resistance against invading microbes: active natural and active artificial.
Naturally acquired active immunity occurs when the person is exposed to a live pathogen, develops the disease, and becomes immune as a result of the primary immune response. Once a microbe penetrates the body’s skin, mucous membranes, or other primary defenses, it interacts with the immune system. B-cells in the body produce antibodies that help to fight against the invading microbes. The adaptive immune response generated against the pathogen takes days or weeks to develop but may be long-lasting, or even lifelong. Wild infection, for example with hepatitis A virus (HAV) and subsequent recovery, gives rise to a natural active immune response usually leading to lifelong protection.
In a similar manner, administration of two doses of hepatitis A vaccine generates an acquired active immune response leading to long-lasting (possibly lifelong) protection. Immunization (commonly referred to as vaccination) is the deliberate induction of an immune response, and represents the single most effective manipulation of the immune system that scientists have developed. Immunizations are successful because they utilize the immune system’s natural specificity as well as its inducibility. The principle behind immunization is to introduce an antigen, derived from a disease-causing organism, that stimulates the immune system to develop protective immunity against that organism, but which does not itself cause the pathogenic effects of that organism.
11.12B: Natural Passive Immunity
Naturally acquired passive immunity occurs during pregnancy, when antibodies are passed from the maternal blood into the fetal bloodstream.
Learning Objectives
• Outline the various ways to obtain passive immunity
Key Points
• Immunity is transferred through the placenta in the form of antibodies, mainly IgG and IgA.
• Natural passive immunity can also be transferred through breast milk.
• Natural passive immunity is short-lived after the birth of the child.
Key Terms
• IgG: immunoglobulin G is an antibody isotype.
• IgA: immunoglobulin A is an antibody isotype.
• passive immunity: the translocation of active humoral immunity from one individual to another in the form of custom-made antibodies.
Immunity is the state of protection against infectious disease conferred either through an immune response generated by immunization or previous infection, or by other non-immunological factors. There are two ways to acquire passive resistance against disease: passive natural and passive artificial. Naturally acquired passive immunity occurs during pregnancy, in which certain antibodies are passed from the maternal blood into the fetal bloodstream in the form of IgG. Antibodies are transferred from one person to another through natural means such as in prenatal and postnatal relationships between mother and child. Some antibodies can cross the placenta and enter the fetal blood. This provides some protection for the child for a short time after birth, but eventually these deteriorate and the infant must rely on its own immune system. Antibodies may also be transferred through breast milk. The transfered IgG from mother to fetus during pregnancy generally lasts 4 to 6 months after birth. The immune responses reach full strength at about age 5.
Passive immunity can also be in the form of IgA and IgG found in human colostrum and milk of babies who are nursed. In addition to the IgA and IgG, human milk also contains: oligosaccharides and mucins that adhere to bacteria and viruses to interfere with their attachment to host cells; lactoferrin to bind iron and make it unavailable to most bacteria; B12 binding protein to deprive bacteria of needed vitamin B12; bifidus factor that promotes the growth of Lactobacillus bifidus, normal flora in the gastrointestinal tract of infants that crowds out harmful bacteria; fibronectin that increases the antimicrobial activity of macrophages and helps repair tissue damage from infection in the gastrointestinal tract; gamma-interferon, a cytokine that enhances the activity of certain immune cells; hormones and growth factors that stimulate the baby’s gastrointestinal tract to mature faster and be less susceptible to infection; and lysozyme to break down peptidoglycan in bacterial cell walls. | textbooks/bio/Microbiology/Microbiology_(Boundless)/11%3A_Immunology/11.12%3A_Classifying_Immunities/11.12A%3A_Natural_Active_Immunity.txt |
Artificial immunity is a mean by which the body is given immunity to a disease by intentional exposure to small quantities of it.
Learning Objectives
• Describe artificially acquired immunity and how it is obtained
Key Points
• The most common form of artificial immunity is classified as active and comes in the form of vaccinations, typically given to children and young adults.
• The passive form of artificial immunity involves introducing an antibody into the system once a person has already been infected with a disease, ultimately relieving the present symptoms of the sickness and preventing re-occurrence.
• Once the body has successfully rid itself of a disease caused by a certain pathogen, a second infection with the same pathogen would prove harmless.
Key Terms
• gamma globulin: a class of proteins in the blood, identified by their position after serum protein electrophoresis, such as antibodies
• anaphylactic shock: A severe and rapid systemic allergic reaction to an allergen, constricting the trachea and preventing breathing.
• herd immunity: the protection given to a community against an epidemic of a contagious disease when a sufficient number of the population are immunised or otherwise develop immunity to it
Immunity is the state of protection against infectious disease conferred either through an immune response generated by immunization or by previous infection or other non-immunological factors.
Artificial immunity can be active or passive.
Artificially-acquired passive immunity is an immediate, but short-term immunization provided by the injection of antibodies, such as gamma globulin, that are not produced by the recipient’s cells. These antibodies are developed in another individual or animal and then injected into another individual. Antiserum is the general term used for preparations that contains antibodies.
Artificial active immunization is where the microbe, or parts of it, are injected into the person before they are able to take it in naturally. If whole microbes are used, they are pre-treated, attenuated vaccines. This vaccine stimulates a primary response against the antigen in the recipient without causing symptoms of the disease.
Artificial passive immunization is normally administered by injection and is used if there has been a recent outbreak of a particular disease or as an emergency treatment for toxicity, as in for tetanus. The antibodies can be produced in animals, called ” serum therapy,” although there is a high chance of anaphylactic shock because of immunity against animal serum itself. Thus, humanized antibodies produced in vitro by cell culture are used instead if available.
The first record of artificial immunity was in relation to a disease known as smallpox. Individuals were exposed to a minor strain of smallpox in a controlled environment. Once their bodies built up a natural immunity or resistance to the weakened strain of smallpox, they became much less likely to become infected with the more deadly strains of the disease. In essence, patients were given the disease in order to help fight it later in life. Although this method was an effective one, the scientists of the time had no real scientific knowledge of why it worked.
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12: Immunology Applications
Learning Objectives
• Describe how artificial and natural passive immunity function to provide antibody protection against microorganisms
There are two types of passive immunity: artificial and natural. Artificial passive immunity is achieved by infusion of serum or plasma containing high concentrations of antibody. This form of passive immunity provides immediate antibody protection against microorganisms such as hepatitis A by administering preformed antibodies. These antibodies have been produced by another person or animal that has been actively immunized, but the ultimate recipient has not produced them. The recipient will only temporarily benefit from passive immunity for as long as the antibodies persist in their circulation.This type of immunity is short acting, and is typically seen in cases where a patient needs immediate protection from a foreign body and cannot form antibodies quickly enough independently.
Passive immunity can also be acquired naturally by the fetus due to the transfer of antibodies by the maternal circulation in utero through the placenta around the third month of gestation. Immunity in newborn babies is only temporary and starts to decrease after the first few weeks, or months. Breast milk also contains antibodies, which means that babies who are breastfed have passive immunity for longer periods of time. The thick, yellowish milk (colostrum) that is produced during the first few days after birth is particularly rich in antibodies. For the newborn to have lasting protection, active immunity must be received. The first immunisation, given when a baby is two months old, includes whooping cough and Hib (haemophilus influenza type b) because immunity to these diseases decreases the fastest. Passive immunity to measles, mumps and rubella (MMR) usually lasts for about a year, which is why the MMR is given just after the baby’s first birthday.
Key Points
• Passive immunization provides humoral immunity.
• Artificial passive immunization is the injection of preformed antibody solution when a patient is incapable of producing antibodies fast enough to combat a disease.
• Natural passive immunization is the transfer of antibodies through the placenta of a pregnant woman to the fetus. Immunity lasts for a couple of months after the baby is born, after which active immunization is required.
Key Terms
• in utero: Occurring or residing within the uterus or womb; unborn.
12.1B: Vaccination
Vaccination is a proven way to prevent and even eradicate widespread outbreaks of life-threatening infectious diseases.
Learning Objectives
• Describe how active immunity to diseases can be acquired by natural exposure or by vaccination
Key Points
• Immunization is the administration of antigenic solution, usually orally or via injection, to protect against infectious bacterial and viral diseases.
• Vaccinations are usually given at specific ages and dates as per the recommended schedule provided by The Center for Disease Control.
• Vaccines stimulate the body to produce antibodies without manifesting clinical signs and symptoms of the disease in immunocompetent hosts.
Key Terms
• toxoids: bacterial toxins whose toxicity has been inactivated or suppressed.
• immunity: the state of being insusceptible to a specific thing.
• immunocompetent: Having a functioning immune system.
Active immunity to diseases can be acquired by natural exposure (in response to actually contracting an infectious disease ) or it may be acquired intentionally, via the administration of an antigen, commonly known as vaccination.
Vaccination has proven to be an effective way to stimulate the human body’s natural ability to produce antibodies, without contracting the disease and suffering any of its effects. This is also known as ‘acquired’ resistance.
The various antigenic materials used in these vaccinations (or immunization) may be of animal or plant origin. Some vaccinations are composed of live suspensions of weak or attenuated cells or viruses, deadened cells or viruses, or extracted bacterial products such as the toxoids used to immunize against diphtheria and tetanus.
Vaccinations are developed to stimulate the body’s production of antibodies without the manifestation of clinical signs and symptoms of the disease in immunocompetent hosts. Moreover, active immunization should cause permanent antigenic memory or lifelong immunity.
Vaccinations are usually given at specific ages and dates according to the recommended schedule provided by The Center for Disease Control. Sometimes booster vaccinations are needed to provide additional immunity in certain individuals and in certain cases.
Once your immune system has been trained to resist a disease, you are said to be immune to it. Before vaccines were developed, the only way to acquire immunity to a disease was to actually get it and, with luck, survive it. Even today, the risk of contracting some of these infectious diseases, like measles and chicken pox, can have devastating, long-term complications, like blindness.
Despite some of the various controversies surrounding vaccines over the years, the tiny proportion of risk is far outweighed by the numerous benefits. Certain infectious diseases, such as Smallpox, have been completely eradicated. Global mass vaccination drives have met with enormous success in reducing the incidence of many diseases.
Another consideration is that the newer vaccination programs also protect older age groups. By these vaccinated children not contracting these diseases, their parents, grandparents, friends and relatives (not vaccinated against these diseases themselves) will also be protected. | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.01%3A_Immunization/12.1A%3A_Passive_Immunization.txt |
New vaccines are being developed to control recent infectious disease epidemics and cancers.
Learning Objectives
• Describe how new vaccines are being developed to help eradicate several infectious global diseases
Key Points
• The World Health Organization (WHO) oversees the development and distribution of vaccines for underdeveloped countries.
• Vaccines for rotavirus diarrhea, pneumococcal disease, and meningococcal infections have been licensed and are approved for development.
• Vaccines for cancer treatment are gaining traction and are based on training the body to recognize cancer cells as foreign.
Key Terms
• vaccine: a substance given to stimulate the body’s production of antibodies and provide immunity against a disease, prepared from the agent that causes the disease, or a synthetic substitute.
• immunization: the process by which an individual is exposed to a material that is designed to prime his or her immune system against that material.
National Immunization Programs
The implementation of large-scale, comprehensive national immunization programs, and the considerable successes that were achieved in the eradication of smallpox and the reduction of polio, measles, pertussis, tetanus, and meningitis, were among the most notable achievements of the 20th century. Even in the poorest countries, immunizations have been able to achieve significant progress in disease control. There is good reason to expect that these advances will be sustained and will progress even further in the 21stcentury.
Vaccines for Infectious Diseases
A number of new vaccines with major potential for controlling infectious diseases have just been licensed or are at advanced stages of development. Among the illnesses targeted are rotavirus diarrhea, pneumococcal disease, and cervical cancer (as caused by human papillomavirus), which together kill more than a million people each year, most of them in developing countries.
In addition to these efforts against global diseases, progress is being made on a vaccine for the regional menace posed by meningococcal meningitis serogroup A, which causes frequent epidemics and high death rates and disability in African countries south of the Sahara. Continuing intensive efforts are under way to develop effective vaccines for AIDS, malaria, tuberculosis, dengue, leishmaniasis, and enteric diseases, among others and to adapt new technologies to improve formulation and delivery. The World Health Organization (WHO) facilitates the development of vaccines against infectious diseases of major public health importance, helps improve existing immunization technologies, and ensures that these advances are made available to the people who need them the most.
12.1D: Vaccine Safety
Vaccines carry risks, ranging from rashes or tenderness at the site of injection to fever-associated seizures.
Learning Objectives
• Describe the possible side effects of vaccine administration
Key Points
• Vaccines can cause side effects in immunocompromised people, and allergic reactions due to the ingredients used to make them stable.
• Side effects from vaccines are rare and most reported ailments after vaccination have not been proven to be caused by vaccination (e.g. autism, asthma).
• Researchers continue to ameliorate vaccines composition making them safer and effective.
Key Terms
• convulsion: An intense, paroxysmal, involuntary muscular contraction.
• subunit vaccine: a vaccine that presents an antigen to the immune system without introducing viral particles, whole or otherwise
• limpness: Property of being limp.
Vaccines are biological products with biological effects. Vaccines are made with a variety of ingredients including antigens, stabilizers, adjuvants, and preservatives; they may also contain residual by-products from the production process. These might be the cause of allergic reactions and side effects.
Vaccines carry risks, ranging from rashes or tenderness at the site of injection to fever-associated seizures called febrile convulsions and dangerous infections in those with compromised immune systems. Technological advances have made modern vaccines purer and safer than their historical counterparts. Most developed countries have switched to the inactivated polio vaccine and stopped using whole-cell pertussis (whooping cough) vaccines, which are made from killed bacteria and cause relatively high rates of arm swelling, febrile convulsions and periods of limpness or unresponsiveness.
Researchers have long known that some individuals are more susceptible to vaccine risks than others. Immunocompromised individuals have generally been discouraged from receiving live-virus vaccines. Some speculate that children with metabolic disorders might be prone to vaccine side effects. Safer vaccines and manufacturing processes are also in the works. New influenza vaccine doses are produced in cell culture, rather than the industry-standard chicken eggs. This process will improve reliability and reduce allergic reactions to egg proteins. Researchers are also developing replacements for vaccines that can be risky for vulnerable groups. These include current smallpox vaccines that cannot safely be given to immunocompromised people; the tuberculosis vaccine, which is not recommended for HIV-positive infants; and the yellow-fever vaccine, which puts elderly people at particular risk of a yellow-fever-like illness. Researchers are quick to emphasize that the benefits of vaccines still greatly outweigh the risks.
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Immunoassays are laboratory techniques based on the detection of antibody production in response to foreign antigens.
Learning Objectives
• Describe how immunoassays aid in the diagnosis of disease
Key Points
• When microbial agents penetrate the body, they elicit an immune response that involves cellular and humoral components.
• An immune response is usually characterized by antibody secretions. These can be measured in the laboratory through various biochemical and serological techniques.
• Most immunoassays rely on the formation of antibody- antigen complexes that can be identified using an indicator molecule.
Key Terms
• humoral: Of or relating to the body fluids or humours.
• antibody: A protein produced by B-lymphocytes that binds to a specific antigen.
The Immune System
Immunology is the study of molecules, cells, and organs that make up the immune system. The function of the immune system is to recognize self antigens from non-self antigens and defend the body against non-self (foreign) agents. Through specific and non-specific defense mechanisms, the body’s immune system is able to react to microbial pathogens and protect against disease. The first line of defense against infection is intact skin, mucosal membrane surfaces, and secretions that prevent pathogens from penetrating into the body.
When a foreign agent penetrates the first line of resistance, an immune reaction is elicited and immune cells are recruited into the site of infection to clear microorganisms and damaged cells by phagocytosis. If the inflammation remains aggravated, antibody-mediated immune reaction is activated and different types of immune cells are engaged to resolve the disease. The immune system is composed of cellular and humoral elements. The cellular component includes mast cells, neutrophils, macrophages, T and B lymphocytes, and plasma cells. The humoral component includes complement, lyzozyme, interferon, antibodies, and cytokines. All work cooperatively to eliminate immunogenic foreign substances from the body.
Immunoassays
To aid in the diagnosis of disease caused by infectious microorganisms, immunoassays have been developed. These biochemical and serological techniques are based on the detection and quantitation of antibodies generated against an infectious agent, a microbe, or non-microbial antigen.
Because antibodies can be produced against any type of macromolecule, antibody-based techniques are useful in identifying molecules in solution or in cells. A blood sample is collected from the patient during the acute phase of the disease when antibody levels are high. Serum is then isolated and the concentration of antibodies is measured through various methods. Most assays rely on the formation of large immune complexes when an antibody binds to a specific antigen which can be detected in solution or in gels. Recent methods employ pure antibodies or antigens that have been immobilized on a platform and that can be measured using an indicator molecule. These methods provide high sensitivity and specificity and have become standard techniques in diagnostic immunology.
12.2B: Antibody Functions
Antibodies, part of the humoral immune response, are involved in pathogen detection and neutralization.
Learning Objectives
• Differentiate among affinity, avidity, and cross-reactivity in antibodies
Key Points
• Antibodies are produced by plasma cells, but, once secreted, can act independently against extracellular pathogen and toxins.
• Antibodies bind to specific antigens on pathogens; this binding can inhibit pathogen infectivity by blocking key extracellular sites, such as receptors involved in host cell entry.
• Antibodies can also induce the innate immune response to destroy a pathogen, by activating phagocytes such as macrophages or neutrophils, which are attracted to antibody-bound cells.
• Affinity describes how strongly a single antibody binds a given antigen, while avidity describes the binding of a multimeric antibody to multiple antigens.
• A multimeric antibody may have individual arms with low affinity, but have high overall avidity due to synergistic effects between binding sites.
• Cross reactivity occurs when an antibody binds to a different-but-similar antigen than the one for which it was raised; this can increase pathogen resistance or result in an autoimmune reaction.
Key Terms
• avidity: the measure of the synergism of the strength individual interactions between proteins
• affinity: the attraction between an antibody and an antigen
Antibody Functions
Differentiated plasma cells are crucial players in the humoral immunity response. The antibodies they secrete are particularly significant against extracellular pathogens and toxins. Once secreted, antibodies circulate freely and act independently of plasma cells. Sometimes, antibodies can be transferred from one individual to another. For instance, a person who has recently produced a successful immune response against a particular disease agent can donate blood to a non-immune recipient, confering temporary immunity through antibodies in the donor’s blood serum. This phenomenon, called passive immunity, also occurs naturally during breastfeeding, which makes breastfed infants highly resistant to infections during the first few months of life.
Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the pathogen that enhance their infectivity, such as receptors that “dock” pathogens on host cells. Antibody neutralization can prevent pathogens from entering and infecting host cells, as opposed to the cytotoxic T-cell-mediated approach of killing cells that are already infected to prevent progression of an established infection. The neutralized antibody-coated pathogens can then be filtered by the spleen and eliminated in urine or feces.
Antibodies also mark pathogens for destruction by phagocytic cells, such as macrophages or neutrophils, because they are highly attracted to macromolecules complexed with antibodies. Phagocytic enhancement by antibodies is called opsonization. In another process, complement fixation, IgM and IgG in serum bind to antigens, providing docking sites onto which sequential complement proteins can bind. The combination of antibodies and complement enhances opsonization even further, promoting rapid clearing of pathogens.
Affinity, avidity, and cross reactivity
Not all antibodies bind with the same strength, specificity, and stability. In fact, antibodies exhibit different affinities (attraction) depending on the molecular complementarity between antigen and antibody molecules. An antibody with a higher affinity for a particular antigen would bind more strongly and stably. It would be expected to present a more challenging defense against the pathogen corresponding to the specific antigen.
The term avidity describes binding by antibody classes that are secreted as joined, multivalent structures (such as IgM and IgA). Although avidity measures the strength of binding, just as affinity does, the avidity is not simply the sum of the affinities of the antibodies in a multimeric structure. The avidity depends on the number of identical binding sites on the antigen being detected, as well as other physical and chemical factors. Typically, multimeric antibodies, such as pentameric IgM, are classified as having lower affinity than monomeric antibodies, but high avidity. Essentially, the fact that multimeric antibodies can bind many antigens simultaneously balances their slightly-lower-binding strength for each antibody/antigen interaction.
Antibodies secreted after binding to one epitope on an antigen may exhibit cross reactivity for the same or similar epitopes on different antigens. Cross reactivity occurs when an antibody binds not to the antigen that elicited its synthesis and secretion, but to a different antigen. Because an epitope corresponds to such a small region (the surface area of about four to six amino acids), it is possible for different macromolecules to exhibit the same molecular identities and orientations over short regions.
Cross reactivity can be beneficial if an individual develops immunity to several related pathogens despite having been exposed to or vaccinated against only one of them. For instance, antibody cross reactivity may occur against the similar surface structures of various Gram-negative bacteria. Conversely, antibodies raised against pathogenic molecular components that resemble self molecules may incorrectly mark host cells for destruction, causing autoimmune damage. Patients who develop systemic lupus erythematosus (SLE) commonly exhibit antibodies that react with their own DNA. These antibodies may have been initially raised against the nucleic acid of microorganisms, but later cross-reacted with self-antigens. This phenomenon is also called molecular mimicry.
12.2C: Serology
Serology is the study of blood serum and other bodily fluids for the identification of antibodies.
Learning Objectives
• Describe how serology can be used to identify antibodies in blood serum and other bodily fluids
Key Points
• Serology is based on detecting immunoglobulin levels during the course of an infection.
• Serological techniques can differentiate between IgM and IgG antibodies, thus determining the stage of the infection.
• Serological techniques are important for the diagnosis of immunological diseases.
Key Terms
• immunoglobulin G: Most abundant antibody isotype secreted by plasma B cells.
• immunoglobulin M: largest antibody produced by B cells and the first to appear in response to initial exposure to antigen.
• serology: the scientific study of blood serum and other bodily fluids.
Serology is the scientific study of blood serum and other bodily fluids. In practical immunological terms, serology is the diagnostic identification of antibodies in the serum. Serological tests are performed on blood serum, and body fluids such as semen and saliva. In practice, the term usually refers to the diagnostic identification of antibodies in the serum or the detection of antigens of infectious agents in serum. Such antibodies are typically formed in response to an infection (against a given microorganism), against other foreign proteins (in response, for example, to a mismatched blood transfusion), or to one’s own proteins (in instances of autoimmune disease).
A primary immune response occurs when a B cell sees an antigen for the first time. Antigen binding to the surface of the B cell stimulates the production of antibodies that are capable of binding directly to the antigen. Because this first recognition process takes time for antibody development, there is an initial delay for the body to fight the invading antigens. Immunoglobulin M (IgM) is an antibody produced during the primary immune response and plays a significant role fighting infection. When an antigen is introduced into the body for the first time, large quantities of IgM are produced. Meanwhile, the B cells are producing highly specific Immunoglobulin G (IgG) more slowly. Once IgG is produced in quantity, the IgG plays a greater role in the removal of antigens from the body due to its ability to bind to the antigen molecules more tightly. Through the course of an infection, a rapid spike of circulating IgM can be seen in the bloodstream. This is followed by a decrease of IgM as the amount of IgG increases. Medical laboratory personnel can identify the course and duration of an infection by measuring the ratio of IgM to IgG in the bloodstream. A ratio high in IgM indicates that an infection is in its early stages, while a ratio high in IgG indicates that the infection is in its later stage. | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.02%3A_Immunoassays_for_Disease/12.2A%3A_Immunoassays_for_Disease.txt |
Precipitation reactions are serological assays for the detection of immunoglobulin levels from the serum of a patient with infection.
Learning Objectives
• Describe how precipitation reactions can be used for the detection of immunoglobulin levels in the serum of a patient
Key Points
• Precipitation assays are performed in semi-solid media such as agar or agarose where antibodies and antigens can diffuse toward one another and form a visible line of precipitation.
• There are several precipitation methods applied in the diagnostic laboratory. These include single, double, and electroimmunodiffusion.
• The most widely used gold standard precipitation methods are Ouchterlony test and Mancini test.
Key Terms
• precipitin: Any antibody which reacts with an antigen to form a precipitate.
Precipitation reactions are based on the interaction of antibodies and antigens. They are based on two soluble reactants that come together to make one insoluble product, the precipitate. These reactions depend on the formation of lattices (cross-links) when antigen and antibody exist in optimal proportions. Excess of either component reduces lattice formation and subsequent precipitation. Precipitation reactions differ from agglutination reactions in the size and solubility of the antigen and sensitivity. Antigens are soluble molecules and larger in size in precipitation reactions. There are several precipitation methods applied in clinical laboratory for the diagnosis of disease. These can be performed in semisolid media such as agar or agarose, or non-gel support media such as cellulose acetate.
Precipitation methods include double immunodiffusion (qualitative gel technique that determines the relationship between antigen and antibody), radial immunodiffusion (semi-quantitation of proteins by gel diffusion using antibody incorporated in agar), and electroimmunodiffusion (variation of the double immunodiffusion method reaction that uses an electric current to enhance the mobility of the reactants toward each other). Precipitation reactions are less sensitive than agglutination reactions but remain gold standard serological techniques. The most commonly used serologic precipitation reactions are the Ouchterlony test (based on double immunodiffusion and named after the Swedish physician who invented it), and the Mancini method (based on single radial immunodiffusion). In the double immunodiffusion technique, three basic reaction patterns result from the relationship of antigens and antibodies. These patterns are identity, non-identity, and partial identity. The Mancini method results in precipitin ring formation on a thin agarose layer. The diameter of the ring correlates with the concentration of proteins in the precipitin.
12.2E: Agglutination Reactions
Agglutination reactions are used to assess the presence of antibodies in a specimen by mixing it with particulate antigens.
Learning Objectives
• Describe how agglutination reactions can be used to assess the presence of antibodies in a specimen
Key Points
• Agglutination reactions produce visible aggregates of antibody – antigen complexes when antibodies or antigens are conjugated to a carrier.
• Carriers used in agglutination methods could be artificial (e.g., latex or charcoal) or biological (e.g., erythrocytes ).
• There are various methods of agglutination reactions that follow the same principle, but they differ in the elements they employ based on the desired endpoint and the main purpose of the test.
Key Terms
• avidity: The measure of the synergism of the strength of individual interactions between proteins.
• erythrocytes: Red blood cells.
• agglutination: the clumping together of red blood cells or bacteria, usually in response to a particular antibody
Agglutination is the visible expression of the aggregation of antigens and antibodies. Agglutination reactions apply to particulate test antigens that have been conjugated to a carrier. The carrier could be artificial (such as latex or charcoal particles) or biological (such as red blood cells). These conjugated particles are reacted with patient serum presumably containing antibodies. The endpoint of the test is the observation of clumps resulting from that antigen-antibody complex formation. The quality of the result is determined by the time of incubation with the antibody source, amount and avidity of the antigen conjugated to the carrier, and conditions of the test environment (e.g., pH and protein concentration). Various methods of agglutination are used in diagnostic immunology and these incude latex agglutination, flocculation tests, direct bacterial agglutination, and hemagglutination.
In latex agglutination, many antibody molecules are bound to latex beads (particles), which increases the number of antigen-binding sites. If an antigen is present in a test specimen, it will bind to the antibody and form visible, cross-linked aggregates. Latex agglutination can also be performed with the antigen conjugated to the beads for testing the presence of antibodies in a serum specimen.
Flocculation tests are designed for antibody detection and are based on the interaction of soluble antigens with antibodies, producing a precipitate of fine particles that can be seen with the naked eye.
Direct bacterial agglutination uses whole pathogens as a source of antigen. It measures the antibody level produced by a host infected with that pathogen. The binding of antibodies to surface antigens on the bacteria results in visible clumps.
Hemagglutination uses erythrocytes as the biological carriers of bacterial antigens, and purified polysaccharides or proteins for determining the presence of corresponding antibodies in a specimen.
Agglutination tests are easy to perform and in some cases are the most sensitive tests currently available. These tests have a wide range of applications in the clinical diagnosis of non- infectious immune disorders and infectious disease. | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.02%3A_Immunoassays_for_Disease/12.2D%3A_Precipitation_Reactions.txt |
Neutralization reactions are used to inactivate viruses and evaluate neutralizing antibodies.
Learning Objectives
• Describe how neutralizing antibodies serve to block viral attachment to cells thus inhibiting viral replication
Key Points
• When a vertebrate is infected with a virus, antibodies are produced against it. Some of the antibodies can block viral infection by neutralization which is usually the result of a formation of a virus-antibody complex. This complex can prevent viral infections in many ways.
• Neutralizing antibodies have shown potential in the treatment of retroviral infections such as HIV. Recently, potent and broadly neutralizing human antibodies against influenza have been reported.
• In diagnostic immunology and virology laboratories, the evaluation of neutralizing antibodies, which destroy the infectivity of viruses, can be measured by the neutralization method.
Key Terms
• neutralization: In the immunological sense refers to the ability of antibodies to block the site(s) on bacteria or viruses that they use to enter their target cell. One example of this within biology is a neutralizing antibody.
• virion: A single individual particle of a virus (the viral equivalent of a cell).
• endosomes: membrane-bound compartments inside eukaryotic cells.
A neutralizing antibody defends a cell from an antigen or infectious body by inhibiting or neutralizing any effect it has biologically. The antibody response is crucial for preventing many viral infections and may also contribute to the resolution of an infection. When a vertebrate is infected with a virus, antibodies are produced against many epitopes of multiple virus proteins. A subset of these antibodies can block viral infection by a process called neutralization. This usually involves the formation of a virus-antibody complex.
This virus-antibody complex can prevent viral infections in many ways. It may interfere with virion binding to receptors, block uptake into cells, prevent uncoating of the genomes in endosomes, or cause aggregation of virus particles. Many enveloped viruses are lysed when antiviral antibodies and serum complement disrupt membranes. Antibodies can also neutralize viral infectivity by binding to cell surface receptors.
Neutralizing antibodies have shown potential in the treatment of retroviral infections. Medical professionals and researchers have shown how the encoding of genes which influence the production of this particular type of antibody could help in the treatment of infections that attack the immune system. Experts in the field have used HIV treatment as an example of infections these antibodies can treat. Recently, potent and broadly neutralizing human antibodies against influenza have been reported, and have suggested possible strategies to generate an improved vaccine that would confer long-lasting immunity. Another disease which has been linked to the production of neutralizing antibodies is multiple sclerosis.
In diagnostic immunology and virology laboratories, the evaluation of neutralizing antibodies, which destroy the infectivity of viruses, can be measured by the neutralization method. In this procedure, patient serum is mixed with a suspension of infectious virus particles of the same type as those suspected of causing disease in the patient. A control suspension of virus is mixed with normal serum and is then inoculated into an appropriate cell culture. If the patient serum contains antibody to the virus, the antibody will bind to the virus particles and prevent them from invading the cells in culture, thereby neutralizing the infectivity of the virus. This technique is labor-intensive, demanding, and time consuming. It application is restricted to laboratories that perform routine viral cultures and related diagnosis. | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.02%3A_Immunoassays_for_Disease/12.2F%3A_Neutralization_Reaction.txt |
Complement fixation is a method that demonstrates antibody presence in patient serum.
Learning Objectives
• Describe how the complement fixation assay can be used to test for the presence of a specific antibody in a patient’s serum
Key Points
• Complement fixation method is more demanding than other systems used to detect antibodies and has been replaced by more sensitive techniques.
• Complement fixation requires several elements mixed together in optimum concentrations.
• The indicator system for the complement fixation assay is sheep red blood cells bound to anti-sheep immunoglobulin G.
Key Terms
• immunoglobulin G: Most abundant antibody isotype secreted by plasma B cells.
Complement fixation is a classic method for demonstrating the presence of antibody in patient serum. The complement fixation test consists of two components. The first component is an indicator system that uses combination of sheep red blood cells, complement-fixing antibody such as immunoglobulin G produced against the sheep red blood cells and an exogenous source of complement usually guinea pig serum. When these elements are mixed in optimum conditions, the anti-sheep antibody binds on the surface of red blood cells. Complement subsequently binds to this antigen -antibody complex formed and will cause the red blood cells to lyse.
The second component is a known antigen and patient serum added to a suspension of sheep red blood cells in addition to complement. These two components of the complement fixation method are tested in sequence. Patient serum is first added to the known antigen, and complement is added to the solution. If the serum contains antibody to the antigen, the resulting antigen-antibody complexes will bind all of the complement. Sheep red blood cells and the anti-sheep antibody are then added. If complement has not been bound by an antigen-antibody complex formed from the patient serum and known antigens, it is available to bind to the indicator system of sheep cells and anti-sheep antibody. Lysis of the indicator sheep red blood cells signifies both a lack of antibody in patient serum and a negative complement fixation test. If the patient’s serum does contain a complement-fixing antibody, a positive result will be indicated by the lack of red blood cell lysis.
12.2H: Fluorescent Antibodies
Fluorescent antibodies are antibodies that have been tagged with a fluorescent compound to facilitate their detection in the laboratory.
Learning Objectives
• Describe how fluorescent antibody conjugates can be used in immunoassays for protein detection
Key Points
• Fluorescent labeling of antibodies is used in place of radioisotopes and enzymes to enhance the sensitivity and specificity of immunological tests.
• Fluorescent antibodies can be used to stain proteins from patient serum or tissue sections fixed on a slide or live cells in suspension.
• Fluorescent antibodies can be detected with a fluorescent microscope or a flow cell sorter.
Key Terms
• radioisotope: A radioactive isotope of an element.
Fluorescent labeling is another method of demonstrating the complexity of antigens and antibodies. Fluorescent molecules are used as substitutes for radioisotope or enzyme labels. The fluorescent antibody technique consists of labeling antibody with dyes such as fluorescein isothiocyanate (FITC). These compounds have high affinity for proteins with which they conjugate.
Fluorescent techniques are very specific and sensitive, so fluorescent antibody-based techniques require a fluorescent microscope. A fluorescent substance absorbs light of one wavelength and emits light of a longer wavelength. Fluorescein fluoresces an intense apple-green color when excited under fluorescent microscopy. The chemical manipulation in labeling antibodies with fluorescent dyes to permit detection by direct microscopy examination does not impair antibody activity.
After the labeling of a specific antibody with a fluorescent molecule, it can still be reacted with its antigen and identified microscopically. Fluorescent antibody conjugates are commonly used in immunoassays. The basic methods utilizing fluorescent antibodies include direct, inhibition, and indirect immunofluorescent assay.
In the direct technique, a fluorescent antibody is used to detect antigen-antibody reactions at a microscopic level. The inhibition immunofluorescent assay is a blocking test in which an antigen is first exposed to an unlabeled antibody, then to a fluorescent antibody, and is finally washed and examined. Indirect immunofluorescence assay is based on the ability of antibodies to react with antigens as well as act as antigens and react with anti-antibody (anti-immunoglobulin). This technique is used extensively for the detection of autoantibodies and antibodies to tissue and cellular antigens. The methods described are mostly performed on glass slides with patient serum or tissue sections. Immunofluorescence can also be performed to identify specific antigens on live cells in suspension. This method is known as flow cytometry and requires a flow cell sorter rather than a fluorescent microscope. | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.02%3A_Immunoassays_for_Disease/12.2G%3A_Complement_Fixation.txt |
Enzyme-linked immunosorbent assay (ELISA) is a solid-phase enzyme immunoassay used to detect the presence of a substance in solution.
Learning Objectives
• Describe how the Enzyme-linked immunosorbent assay (ELISA) can be used to detect and quantitate antigens, antibodies and allergens
Key Points
• ELISA is a quantitative technique that measures serum concentration of antigens, antibodies, and allergens.
• Standard ELISA uses antibody-antigen-antibody trapping principle with the second antibody coupled to an enzyme. If the complex is formed, the enzyme converts a clear solution into a colored one that can be measured with a spectrophotometer.
• ELISA is performed in a muti-well microtiter plate. In addition to the test solution, standard solutions are added with known antigen concentration. These solutions will be used to infer the concentration of the antigen being tested.
Key Terms
• spectrophotometrically: By using spectrophotometry.
• epitope: That part of a biomolecule (such as a protein) that is the target of an immune response.
Enzyme-linked immunosorbent assay (ELISA) is a method of quantifying an antigen immobilized on a solid surface. ELISA uses a specific antibody with a covalently coupled enzyme. The amount of antibody that binds the antigen is proportional to the amount of antigen present, which is determined by spectrophotometrically measuring the conversion of a clear substance to a colored product by the coupled enzyme.
Several variations of ELISA, seen in, exist but the most commonly used method is the sandwich ELISA. The sandwich assay uses two different antibodies that are reactive with different epitopes on the antigen with a concentration that needs to be determined. A fixed quantity of one antibody is attached to a series of replicate solid supports, such as plastic microtiter multi-well plate. Test solutions containing antigen at an unknown concentration are added to the wells and allowed to bind. Unbound antigen is removed by washing, and a second antibody which is linked to an enzyme is allowed to bind. This second antibody-enzyme complex constitutes the indicator system of the test. The antigen serves as bridge, so the more antigen in the test solution, the more enzyme-linked antibody will bind. The test solution is used in parallel with a series of standard solutions with known concentrations of antigen that serve as control and reference. The results obtained from the standard solutions are used to construct a binding curve of the second antibody as a function of antigen concentration. The concentration of antigens can be inferred from absorbance readings of standard solutions.
12.2J: Immunoblot Procedures
Immunoblot is a technique for analyzing proteins via antigen-antibody specific reactions.
Learning Objectives
• Describe how Western blotting allows individuals to detect specific solubilized proteins from serum or cell or tissue extracts
Key Points
• In immunoblot techniques such as Western blot analysis, proteins are separated by electrophoresis and transferred onto nitrocellulose sheets, then are identified by their reaction with labeled antibodies.
• Electrophoresis uses an electric current to separate proteins based on their size. Big proteins migrate slower and are represented by the highest bands on the blot, while small proteins migrate faster and are indicated by the lowest bands on the blot.
• Immunoblot assays are usually performed to confirm results obtained by other techniques such as ELISA.
Key Terms
• sodium dodecyl sulfate: strong detergent agent used to reduce and unfold native protein.
• blot: method of transferring protein, DNA, or RNA onto a carrier membrane.
Immunoblot procedures like protein blotting, or Western blotting, allow individuals to detect specific solubilized proteins from extracts made from cells or tissues, before or after any purification steps.
Immunoblotting Procedures
This analytic technique proceeds in the following steps. Proteins are generally separated by size using sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. After this, they are transferred to a synthetic membrane via dry, semi-dry, or wet blotting methods. In the electric field generated by a power supply, the proteins coated with negatively charged SDS migrate toward the positive electrode. As the proteins migrate out of the gel, they are captured on a membrane. Protein binding to the membrane is an irreversible mechanism. Membranes can be of the nitrocellulose, polyvinylidene difluoride (PVDF), or nylon variety. The membrane can then be blocked with serum albumin or milk solution to prevent non-specific antibody binding. This is followed by probing with antibodies specific to the protein being studied on the membrane, a method that is similar to immunohistochemistry, but without a need for fixation. This technique exploits the specificity inherent in antigen-antibody recognition. Detection is typically performed using chromogen or peroxide-linked secondary antibodies to catalyze a chromogenic or chemiluminescent reaction.
Applications of Immunoblotting
Western blotting is a routine molecular biology method that can be used to semi-quantitatively compare protein levels between extracts. The size separation, prior to blotting, allows the protein molecular weight to be gauged, as compared with known molecular weight markers. Immunoblots are most often used in research settings and are usually performed to confirm results from ELISA or other immunoassays. In clinical diagnostic settings, immunoelectrophoresis is applied, which involves the electrophoresis of serum or urine followed by immunodiffusion. The size and position of precipitation bands provides the same type of information about antibody amount as the double immunodiffusion method. | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.02%3A_Immunoassays_for_Disease/12.2I%3A_Enzyme-Linked_Immunosorbent_Assay_%28ELISA%29.txt |
Methods used to differentiate T cells and B cells include staining cell surface receptors and functional assays like the T lymphocyte cytotoxicity assay.
Learning Objectives
• Describe how T cells and B cells can be differentiated using staining of cell surface receptors and functional assays like the T lymphocyte cytotoxicity assay
Key Points
• There are two types of lymphocytes: B cells and T cells. These two components of the immune system have different functions but cooperate to fight infection.
• T cells elicit cell-mediated immune response, while B cells elicit humoral immunity.
• Lymphocytes are the only immunologically specific cellular components of the immune system.
Key Terms
• cytotoxic: of, relating to, or being a cytotoxin
Lymphocytes are the only immunologically specific cellular components of the immune system. They are divided into two types based on the pathogen recognition receptors they express on their surface. T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes. They are called T cells because they mature in the thymus. They play a central role in cell-mediated immunity along with initiating rejection of foreign tissues following organ transplantation. B-cells are also white blood cells and are a vital part of the humoral immunity branch of the adaptive immune system. These two cell types can function independently or cooperatively to defend the body against pathogens. T-lymphocytes can be distinguished from other lymphocytes like B cells and natural killer cells (NK cells) by the presence of a T cell receptor (TCR) on the cell surface. Alternatively, B-cells can be distinguished from other lymphocytes like T cells and natural killer cells (NK cells) by the presence of a protein on the B-cell’s outer surface called a B-cell receptor (BCR).
Traditionally, T-lymphocytes were defined by their ability to form E-rosettes when they bind selectively to sheep erythrocytes. T-lymphocytes express CD3, CD4, CD8, or CD25 markers. B-lymphocytes express CD19 marker. The expression of different markers allows the separation/ differentiation of T and B cells. Another functional assay used to identify T-lymphocyte is the cytotoxic activity assay. This assay is based on measuring the killing ability that a determined number of T lymphocytes have for a certain number of target cells when both populations are placed together. B-lymphocytes have membrane-bound immunoglobulins that can be stained with anti-immunoglobulin labeled with fluorescent dyes and detected with a fluorescent microscope. More modern techniques like flow cytometry and immunohistochemistry are commonly used and rely on the use of fluorescent antibodies. These techniques are based on staining B and T cells for unique cell surface markers known as cluster of differentiation (CD).
12.2L: In Vivo Testing
In vivo testing using animal models of disease help discover new ways of solving complex health problems.
Learning Objectives
• Describe how animals can be used for diagnostic antibody production
Key Points
• In vivo testing is necessary for medical and research purposes. The medical field benefits from animal models to test the safety of drugs before they are used on patients. The research field benefits from in vivo testing by validating in vitro findings in vertebrates closest to humans.
• The most used animal models are mice, rats, and other rodents.
• In vivo testing is useful for the production of polyclonal antibodies applied in immunoassays and diagnostic immunology.
Key Terms
• in vitro: In an artificial environment outside the living organism.
• antiserum: a serum prepared from human or animal sources containing antigens specific for combatting an infectious disease
• in vivo: Within a living organism.
In Vivo Testing
In vivo methods refer to the use of animals as a conduit to generate purified polyclonal antibody solutions ( antiserum ) for research purposes. Polyclonal antibodies are applied in immunological assays to diagnose disease.
In vivo testing follows strict guidelines and humane animal use ethics. The protocol for diagnostic antibody production in animals follows multiple steps. Animals are injected with microbes or antigenic fragments that elicit an immune response; the immune response is allowed to develop for 1-2 weeks, after which blood is harvested. This blood now contains antibodies created from the antigens that were introduced into the animals. Antibodies are purified from the serum to make antiserum or a purified antibody solution for one particular antigen.
These preparations will produce multiple antibody types that recognize different epitopes on the antigen, hence the term polyclonal. Polyclonal antibodies have various applications in the clinic and in research laboratories. Animals are also used to model human diseases in the research field. They are useful vehicles to understand how our bodies work, find cures and treatments for diseases, test new drugs for safety, and evaluate medical procedures before they are used on patients.
Mice, and other rodents such as rats and hamsters, make up over 90% of the animals used in biomedical research. In addition to having bodies that work similar to humans and other animals, rodents are small in size, easy to handle, relatively inexpensive to buy and keep, and produce many offspring in a short period of time. In vivo testing remains a crucial step for the evaluation of in vitro experimental findings and the production of immunological solutions needed for the diagnosis of human diseases. | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.02%3A_Immunoassays_for_Disease/12.2K%3A_Tests_That_Differentiate_Between_T_Cells_and_B_cells.txt |
The future of diagnostic immunology lies in the production of specific antibody-based assays and the development of improved vaccines.
Learning Objectives
• Describe how immunologic methods are used in the treatment and prevention of infectious diseases and immune-mediated diseases
Key Points
• Diagnostic immunology has considerably advanced due to the development of automated methods.
• New technology takes into account saving samples, reagents, and reducing cost.
• The future of diagnostic immunology faces challenges in the vaccination field for protection against HIV and as anti-cancer therapy.
Key Terms
• ELISA: enzyme-linked immunosorbent assay; assay based on the principle of antibody-antigen interaction.
The Future of Diagnostic Immunology
Modern immunology relies heavily on the use of antibodies as highly specific laboratory reagents. The diagnosis of infectious diseases, the successful outcome of transfusions and transplantations, and the availability of biochemical and hematologic assays with extraordinary specificity and sensitivity capabilities all attest to the value of antibody detection.
Immunologic methods are used in the treatment and prevention of infectious diseases and in the large number of immune -mediated diseases. Advances in diagnostic immunology are largely driven by instrumentation, automation, and the implementation of less complex and more standardized procedures. Examples of such processes are as follows:
• miniaturization (use of microtiter plates to save samples and reagents),
• amplified immunoassays (chemiluminesent ELISA),
• flow cytometry with monoclonal antibodies,
• immunoglobulins,
• molecular methods (polymerase chain reactions).
These methods have facilitated the performance of tests and have greatly expanded the information that can be developed by a clinical laboratory. The tests are now used for clinical diagnosis and the monitoring of therapies and patient responses. Immunology is a relatively young science and there is still so much to discover. Immunologists work in many different disease areas today that include allergy, autoimmunity, immunodeficiency, transplantation, and cancer.
Interestingly, no matter what the areas of expertise, vaccine development and understanding how vaccines work pose the greatest challenges. The vaccines currently used primarily generate an antibody response, which is able to attack free-moving pathogens, but is unable to fight bacteria and viruses, such as human immunodeficiency virus (HIV). In the cancer research field, vaccines that stimulate the immune system to attack tumor cells are undergoing clinical trials.
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• Clipart - Chemical Flasks. Provided by: Open ClipArt. Located at: http://openclipart.org/detail/3607/-by--3607. License: Public Domain: No Known Copyright | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.02%3A_Immunoassays_for_Disease/12.2M%3A_The_Future_of_Diagnostic_Immunology.txt |
Laboratory diagnosis of diseases begins with the collection of a clinical specimen for examination or processing in the laboratory.
Learning Objectives
• Describe how laboratory diagnosis of disease begins with the collection of a clinical specimen for examination and processing
Key Points
• Specimen collection requires withdrawing blood, cerebrospinal fluid, collecting urine, or swabs from mucosal surfaces.
• Specimen collection is performed using aseptic techniques to ensure sterility of the sample and avoid contamination from bacteria or other bodily fluids.
• The types of biological samples accepted in most clinical laboratories are: serum samples, virology swab samples, biopsy and necropsy tissue, cerebrospinal fluid, whole blood for PCR, and urine samples. These are collected in specific containers for successful processing in the laboratory.
Key Terms
• PCR: polymerase chain reaction
• necropsy: The pathological dissection of a corpse; particularly to determine cause of death. Applicable to the examination of any life form.
• biopsy: The removal and examination of a sample of tissue from a living body for diagnostic purposes.
Laboratory diagnosis of an infectious disease begins with the collection of a clinical specimen for examination or processing in the laboratory.
The laboratory, with the help of well-chosen techniques and methods for rapid isolation and identification, confirms the diagnosis.
It has been observed that the most important and frequent factor affecting laboratory analysis, even in a well-functioning laboratory, is not the laboratory investigation itself but specimen preparation and errors in identification or labeling. Proper collection of an appropriate clinical specimen is, hence, the first step in obtaining an accurate laboratory diagnosis of an infectious disease.
Applying one’s knowledge of microbiology and immunology for the collection, transportation and storage of specimens is as important as it is in the laboratory. For starters, the interpretation of the observation may be misleading if the specimen is inadequate.
There are several types of specimens recommended for diagnosis of immunological diseases including: serum samples, virology swab samples, biopsy and necropsy tissue, cerebrospinal fluid, whole blood for PCR, and urine samples.
Serum is the preferred specimen source for serologic testing. Blood specimens are obtained aseptically using approved venipuncture techniques by qualified personnel. Specimens are allowed to clot at room temperature and then are centrifuged. Serum is transferred to tightly-closing plastic tubes and stored at 2 – 8°C before shipment–which should always be prompt. Acute serum should be collected at the onset of symptoms. Convalescent specimens should follow two to four weeks later. Paired sera are tested together.
Plasma is also collected for a very limited number of tests. Lipemic, hemolyzed, or contaminated sera may cause erroneous results and should be avoided as should repeated freeze-thaw cycles.
Another type of specimen used for disease diagnosis is cerebrospinal fluid (CSF). This should be transported in tightly-closing plastic tubes. Refrigerated CSF is acceptable for a limited number of serologic tests; however, if PCR is to be performed for the viral panels, the specimen must be frozen and shipped on dry ice. CSF specimens should be clear of any visible contamination or blood. A lumbar puncture (or LP, and colloquially known as a spinal tap) is performed to collecte CSF. This consists of the insertion of a hollow needle beneath the arachnoid membrane of the spinal cord in the lumbar region to withdraw cerebrospinal fluid for diagnostic purposes or to administer medication. | textbooks/bio/Microbiology/Microbiology_(Boundless)/12%3A_Immunology_Applications/12.03%3A_Preparations_for_Diagnosing_Infection/12.3A%3A_Specimen_Collection.txt |
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