polymorphonuclear leukocytes ( pmns ) ( neutrophils ) are phagocytic cells that are able to kill pathogens ; elimination by these cells is a major innate host defense mechanism . in the case of healthy individuals , however , in hospitalized patients , particularly those with compromised immune systems , this bacterium is a major cause of morbidity and mortality . it is also the leading bacterial cause of acute ventilator - associated pneumonia and chronic lung infections in patients with cystic fibrosis ( cf ) . defining the dysfunction of neutrophils in susceptible individuals provides the basis for understanding normal host responses to p. aeruginosa . furthermore , recognition of bacterial factors that promote resistance to pmn killing may help identify therapeutic targets for this important opportunistic pathogen . the breakdown of normal innate immune function results in increased susceptibility to p. aeruginosa . unless there is compromise , either at a mucosal surface or by immune defects , healthy humans are generally able to resist becoming infected with this bacterium . patients undergoing chemotherapy are particularly susceptible to p. aeruginosa , which can lead to life - threatening pneumonia and bacteremia . mice have been used as a model organism for this type of compromise : treatment with the chemotherapeutic agent , cyclophosphamide ( cy ) or an antibody generally specific for neutrophils , rb6 - 8c5 ( also known as anti - gr1 ) , results in mice that are considered leukopenic or neutropenic , respectively . a lethal infection of these immunocompromised mice can be achieved by intranasal administration of a dose of bacteria that is more than 6 logs lower than that needed to cause a similar infection in mice with intact immune function . the p. aeruginosa strain used in these studies did not contain the cytotoxic phospholipase , exou , and thus does not readily disseminate in normal mice except at very high doses   but was found in the liver and spleen of the immunocompromised mice at a very low dose . this was not due to increased lung permeability by the immunocompromise itself but was a result of both cy treatment and p. aeruginosa infection . similar dissemination from the gastrointestinal tract of p. aeruginosa colonized mice was seen after cy or rb6 - 8c5 treatment . this suggests that the combination of immunocompromise and p. aeruginosa promotes the dissemination that is characteristic of this devastating infection in patients undergoing chemotherapy . while exou is apparently not required for infection in immunocompromised hosts , p. aeruginosa strains that express exou and the type iii secretion system have been associated with poor outcomes in patients with hospital - acquired and ventilator - associated pneumonia [ 4 - 6 ] . in fact , it has been shown recently that exou itself interferes with the ability of recruited phagocytic cells to eradicate bacteria from the lung , thus promoting additional immunosuppression . recently , koh et al .   repeated similar low challenges with multiple p. aeruginosa strains in cy- or rb6 - 8c5-treated mice and observed the same increased susceptibility . reconstitution of neutrophils by recombinant murine granulocyte colony - stimulating factor partially restored host resistance to infection , implicating these cells as critical immune effectors . myd88 mice , which can not recruit neutrophils to the lung , were also highly susceptible to p. aeruginosa infection . interestingly , mice lacking functional lymphocytes ( rag ) were only slightly more susceptible to infection than wild - type mice , but those depleted for resident alveolar macrophages did not show increased susceptibility . these findings suggest that the recruitment of neutrophils to the lung may be a reasonable approach to augment host resistance to p. aeruginosa infections . other studies indicate that such recruitment must be carefully timed with respect to the infection process as the effects of neutrophils themselves can be detrimental if attuned inappropriately . patients with cf are particularly susceptible to infections with p. aeruginosa but are not generally considered immunocompromised . while a defective cf transmembrane conductance regulator ( cftr ) gene can affect virtually all cell types , studies of neutrophils from patients with cf continue to implicate these cells as critical players in the susceptibility to chronic lung infection by p. aeruginosa . dysregulation of various neutrophil functions in cf results in decreased bacterial killing as well as persistent neutrophil influx to the airways , leading to increased lung damage ( reviewed in [ 10 - 12 ] ) . it remains controversial whether abnormalities exist in the oxidative responses of these neutrophils compared with those from healthy individuals . microarray analysis of neutrophils from children with cf has indicated that these cells show a distinctive pattern of gene expression compared with cells from healthy young adults ; however , as none of the subjects in this study tested positive for p. aeruginosa , the effects in the context of infection were not considered . for example , cf neutrophils secrete increased levels of neutrophil elastase ( ne ) compared with cells from healthy subjects . while ne is generally considered a contributor to tissue damage associated with p. aeruginosa infection , neutrophils from ne - deficient mice are less able to kill p. aeruginosa than those from wild - type mice . also , ne - deficient mice are more susceptible to infection , and as this is not due to a defect in recruitment , it suggests an important role for ne in innate defense . similar effects were seen with mice lacking the neutrophil serine protease inhibitor , serpinb1 , which dampens the activity of ne and other proteases . aeruginosa killing by neutrophils from normal donors and cf patients was recently measured by painter et al . . in addition to finding that cf neutrophils had a significantly lower rate of killing , these authors went on to show that inhibition of cftr itself blocked p. aeruginosa killing , implicating this protein as an important component of neutrophil function . studies have shown that among the toll - like receptors ( tlrs ) tested , only tlr-5 is surface - expressed and upregulated on the airway neutrophils of patients with cf compared with those of healthy individuals . however , since chronic p. aeruginosa isolates from patients with cf show decreased flagella expression ( one mechanism being the suppression of transcription of flagellin by ne ) , there is ligand - receptor mismatch and therefore impaired neutrophil function ( reviewed in ) . the importance of other tlrs in neutrophil function and p. aeruginosa susceptibility has not been as thoroughly investigated . ( reviewed in ) showed that interleukin-8 ( il-8 ) binds to cxcr1 , a g protein - coupled chemokine receptor ( also known as il-8ra ) , to promote pmn - mediated killing of p. aeruginosa . however , cxcr1 on neutrophils from the airways of patients with cf was found to be proteolytically cleaved . this degraded receptor led to defects in the bactericidal capacity of neutrophils . in addition , the cleaved receptor fragments induced large amounts of il-8 in the airways , which recruited more neutrophils , setting up a vicious cycle of airway inflammation in cf . while numerous secreted and injected enzymes produced by p. aeruginosa can affect epithelial and other cells ( reviewed in ) , particular p. aeruginosa factors can protect the bacterium from neutrophil - mediated killing . while the polysaccharide alginate is well known for its anti - phagocytic properties , p. aeruginosa rhamnolipids have recently been shown to cause necrotic death of pmns , resulting in reduced clearance of the bacteria . the expression of rhamnolipids is controlled through the p. aeruginosa quorum - sensing system , and microarray studies have revealed that this system is itself activated in the presence of pmns . also , it was shown that biofilms formed in the presence of pmns produced more rhamnolipids . thus , p. aeruginosa can provide itself with a protective shield from neutrophils ( reviewed in ) . the persistent accumulation and lysis of neutrophils can lead to uncontrolled release of granule proteins , dna , and actin from necrotic cells . these latter two factors have been shown to be important for biofilm development [ 27 - 29 ] . these findings suggest that these components could be important targets for anti - biofilm and anti - pseudomonal therapy ( reviewed in ) . it is now appreciated that p. aeruginosa strains with distinct genotypes and phenotypes can be recognized in the natural environment and different types of infections [ 31 - 35 ] . in addition to recent p. aeruginosa transcriptome analysis ( reviewed in ) and metabolic pathway studies , future investigations should be extended to include multiple p. aeruginosa strains as well as polymicrobial communities present in the environment and in infection . the natural and acquired antibiotic resistance of p. aeruginosa makes infections by this bacterium extremely difficult to treat , and thus the search is on to identify mechanisms or molecules to increase sensitivity to antibiotics . also , there is a push to find inhibitors of the synthesis or regulation ( or both ) of factors critical for virulence . it is a breakdown in the normal host response that is responsible for most of the susceptibility to infection with this bacterium . while the importance of alveolar macrophages and other cells remains controversial , the presence of neutrophils is required for protection from infection . however , the appropriate regulation of neutrophil function is critical for a productive response . studies of neutrophils from cf and other immunodeficient patients have begun to define the pathways and molecules critical for an effective innate immune response . these studies have also shown that that there is a delicate interplay between p. aeruginosa and the host to resolve an infection . to define these interactions in more detail , future investigations using human neutrophils   in the context of p. aeruginosa infection could be even more informative . such studies may help identify mechanisms to promote a more effective innate host response in susceptible individuals and therefore provide protection from infections by this important pathogen .
despite the expression of a myriad of virulence factors , healthy individuals are generally able to resist infections with pseudomonas aeruginosa . 
 polymorphonuclear leukocyte - dependent killing is the major mechanism responsible for resistance ; dysregulation of host defense mechanisms in addition to expression of specific bacterial factors can result in life - threatening infections with this bacterium .