Coronaviruses are group of enveloped viruses with positive sense RNA as the genetic material, containing 20-30kbp genome. These viruses cause mild respiratory and intestinal infections in immune compromised individuals. They were not considered to be pathogenic until the outbreak of Severe Acute Respiratory Syndrome (SARS) in china and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Middle East countries in 2002 and 2012 respectively when the viral infection led to significant deaths among the infected individuals. The novel emerging pneumonic virus generally referred as 2019-nCov.
Corona virus belongs to coronaviridae family, which includes 4 different lineages, i.e., alpha, beta, delta and gamma corona viruses. There are seven strains of corona virus of alpha and beta genera that likely to cause pathogenicity in humans, in which four of them namely 229E, OC43, HKU1 and NL63 cause common cold, pneumonia and 10-30% upper respiratory tract infections across worldwide [13]. The other three highly morbific MERS-CoV, SARS-CoV, 2019-nCoV infect lower airways and cause fatal pneumonia, organ damage and high mortality rate [14].
Severe acute respiratory syndrome (SARS) corona virus was first sensed in Guangdong, china in November 2002. The seriousness of this virus was quite evident from this fact that were 8,098 confirmed cases and 774 deaths with Mortality rate of 10%, which affected approximately 29 countries including Hong kong, Torronto in Canada, Singapore, Hanoi in Vietnam etc[15]. The emergence of this disease was believed to be originated from bats passed on to civets and then transmitted to humans [17].
Middle Eastern Respiratory Syndrome (MERS) was first reported in Saudi Arabia in the year of 2012. The devastation from MERS CoV was more terrible, had 2494 confirmed cases and 858 deaths with mortality rate of 34%, far more than SARS. Besides Saudi Arabia, 24 countries were also affected which includes Korea, United States of America, Iran, Kuwait, Iraq etc. The original source of epidemic was found to be infected camel, transmitted to humans by touching, consuming their milk or meat [15]. The infection was caused by similar spike S protein, but the receptor is different in the case of MERS. Attachment of glycoprotein occurred with cell receptor Dipeptidyl peptidase-4 (DP4) [16].
These three lineages of CoV followed the same mechanism for their zoonotic infection, as viral particle was originated from the same animal sources (bats in case of SARS, MERS) and then spill-over from host animals to humans occurred (civets in SARS and Camels inn MERS) [17]. This was not clear for nCoV, but there is still discussion going on over this. Their initial symptoms also found to be same include fever, cough, pneumonia, diarrhea etc. The reproductive ratio (Reproductive number, R0 ) found to be 2.2 in nCoV , 2-3 in SARS, 0.7 in MERS [24]. The number of cases generated from one in a susceptible population was almost similar in 2019-nCoV and SARS, but was higher compared to MERS.
INTRODUCTION OF 2019 n-CoV
Human corona viruses have been shown to be rapidly evolving due to high genomic nucleotide substitution rate as well as recombination (Ref 1). Apart from evolution, viral transmission is further fuelled by rapid urbanisation and close animal human encounters. With the use of Bioinformatics approach, Genomic analyisis of the viral samples taken from various infected patients was done [11]. Result showed 89.9% and 82% nucleotide idenitity with the bat SARS-like-CoVZXC21 (betacoronavirus) and human SARS-CoV respectively. Their position in phylogentic tree also closely converged on basis of their orf1a/b, Spike, Envelope, Membrane and Nucleoprotein. The culmination of both emphasized that the original source of nCoV might be bats betavirus lineages, circulated in wuhan south China seafood market where emergence of transmission of novel virus thought to occur. The WHO report claimed that the food samples of the market was contaminated with the novel corona viral particles but the associated animal source is not yet identified. Some early research also found that recombination within the spike glycoprotein of nCoV occurred that might be the reason for cross transmission from snakes to humans, validated by the relative synonyms codon usage bias. This lead to this conclusion that snakes were likely to be the cause of spillover of nCov [12]. Snake meat, the main attraction of wuhan sea food market, jump the nCoV from bats to snakes and led to the outbreak of the novel corona virus [16]. From recent report, it is cleared that 49% of the patients in china consumed food from wuhan sea food market [18].
The study on SARS corona virus (2002) revealed that the pathogenicity of virus caused by the interactions of SARS-CoV spike protein, having receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme-2 (ACE2), a metallopeptidase. Although the spikes glycoproteins are the part of envelope on the viral surface, their attachment to the receptor leads entry and replication in the host cell. From the recent publication of Chan JF et. al. showed that the structural differences seen in the external subdomain of Spike's receptor binding domain of 2019-nCoV, a novel short protein translated by orf3b that is not present in other beta corona virus lineages [11]. The genomic analysis depicts that there is only 40% amino acid identity between the Receptor binding Domain of Spike proteins, when compared to the other SARS corona viruses. This high percentage of dissimilarity cause major changes in the spike protein sequence and ultimately the conformation, which could be a reason for the viruses to target humans, animals as their host other than bats [11].
A recent publication of Shen Yongyi and Xiao Lihua also suggested that the bats coronavirus having 82-89% genomic identity were not the original source, instead pangolins found to be the potential source of nCoV. Coronavirus traces from pangolins and humans were taken and their genomic characterization showed 99% similarity [25]. Illegal tracking for their meat and scales, and infection from Coronavirus lineages are the main cause for decreasing population of pangolins.
Global distribution of coronaviruses
Since the outbreak of the virus in December 2019, in Wuhan, China, people infected with this mysterious new coronavirus are escalating fast. As of 8 feburary 2020, 34,546 cases were confirmed and around 722 people were reported dead in china. Although most of the cases are confined to China, the virus has been able to spread in globally with some cases reported in United States of America, Hong Kong, Malaysia, France, Australia, Thailand, South Korea, Taiwan, Macau, Japan and the Philippines. Apart from China, United Kingdom witnessed most of the infected cases. Migration from China was the main cause for the secondary transmission across the world. Travelers from China, developed some pneumonic like symptoms, fever, distress, breathlessness within 14 days. Some reports indicated possible infections among two people in India who were studying in Wuhan and had returned back home. And experts all over the world are on high alert after authorities confirmed that the virus could jump from human to human. The WHO has declared Public Health Emergency of International concern on 30th January, 2020 in response to its rising.
Human corona virus cause disease at average age around 45 years, but can affect 2-74 years of age. People having earlier medical history of diabetes, coronary health diseases, asthma, parkinson’s disease found to be more prone to this virus. The ratio of affected males and females is surprisingly very contrasting. This novel virus showed symptoms more in males (71% of total cases) according to recent report [1001]. The justification of this unpredicted data was revealed in recent publication, shown that the ACE-2 expressing cells are more in number in males than females approximately ratio of 5:2-4 cells number.[111] Since receptors of 2019-nCoV are present largely in males, so the most of the infected patients and deaths were seen of males. This report also enlightened that the presence of ACE-2 receptors also varies according to the geographical convention. Asian population has a large impact of this novel virus, whereas African American population exhibit only about 0.47% ACE-2 expressing cells. The history of 2002 and 2012 pandemic make this quite evident that the origin of the corona family viruses was from the Asiatic countries. So the Asian people have much higher amount of ACE-2 expressing cells, i.e., 2.5% of total.
This novel virus created fear among people of China and other countries because of its asymptomatic (symptomless) transmission. The virus is transmitted mainly through inhalation of air droplets and even by casual touching, sneezing, shaking hands. People of China are keeping themselves safe by making the use of N95 mask that blocks inhalation of 95% air particles including virus. Recent research claimed that ocular transmission of 2019-nCoV was also occurred in china. Guangfa wang (member of pneumonic National expert panel) protecting himself by N95 mask but he observed redness in eyes after inspection for several days in hospitals. The infection was caused because of his uncovered eyes[22]. Conjuctival scraping done from infected and suspected patients and proved that eyes are also the route of transmission besides respiratory tract.
Clinical symptoms of novel coronavirus
The initial clinical symptoms detected from the records of 59 patients admitted in Wuhan hospital appeared to be distress, fever, dry cough, dysponea and CT San of lungs showing Bilateral opacities (filling of alveolar cells partially) [19] showing Acute respiratory syndrome. Viral particle traces seen in patients blood samples and broncho-alveolar lavage fluid (BALF).
The first emergence of SARC-CoV was characterised by a typical pneumonia followed by fever headache and onset of mild respiratory symptoms which could later develop into life threatening syndromes. Recent study by Yu zhao et.al. [111] shown that, upon immunostaining levels of ACE-2 proteins rapidly increases in type 2 alveolar cells in the lower airways of lungs in infected patients, therefore virus enter these cells and bind to their ACE-2 receptor. Since viral particle residing in the alveolar cells perform their replication machinery, so the lungs are the prime suspect of these nCoV causing pneumonia and in severe cases lungs damage [111]. Other intestinal related symptoms like diarrhea was not seen in 2019-nCoV, but these symptoms were majorly observed in 20-25% of SARS and MERS cases [19].
Pulmonary infections and damage simultaneously leads to elevated levels of cytokines in beta corona virus infections. IL6, IL12, IFN-γ, IP10, MCP-1 cytokines level increases in SARS and IFN-γ, TNF-α, IL15, IL17 in MERS. The levels of these pro-inflammatory cytokines was also observed in 2019-nCoV and leads to activation of T-Helper cells ,mainly by IL1B, IP10, IFN-γ, MCP-1. But also IL4 and IL10 (TH-2 cytokines) levels raised, that assist in immune reactions [19].
Treatment of 2019-nCoV in itself is a big controversy, some research claimed that corticosteroid intake is not helping in this treatment, and even making it more worse which showed positive result in SARS and MERS infection [21] .Some FAD approved drugs were found to be very effective in treatment of nCoV inflammation. Drugs include Remdisiver (Adenosine analogue), Chloroquine (interfere with entry of virus), Nafamostat (interfere with membrane attachment), Favipiravir, Nitazoxanide gives positive impact by blocking their action of mechanism [21].
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