© 2008 American Thoracic Society doi: 10.1164/rccm.200805-789ED
Pseudomonas aeruginosaAn Uninvited Guest Refuses to Leave
Northwestern University Pseudomonas aeruginosa has long been an unwelcome guest in the intensive care unit. Both a frequent and serious cause of ventilator-associated pneumonia (VAP), this organism causes infections that are especially difficult to treat. For example, VAP caused by P. aeruginosa is associated with attributable mortality rates of 40%, higher than the corresponding rates for most other causes of VAP (1–4). Even patients who recover with the aid of appropriate antimicrobial therapy have an 18% chance of experiencing a relapse (1). These alarming figures are no doubt partly due to this bacterium's propensity to develop resistance to commonly used antibiotics, but the intrinsic virulence of P. aeruginosa has also been hypothesized to play a role. Clues as to why P. aeruginosa is associated with such poor outcomes in the context of VAP are beginning to emerge. For example, studies have shown that, even when treated with antimicrobial agents to which it was initially susceptible, P. aeruginosa persisted in the lungs of some patients with VAP for up to 15 days, a finding not as frequently observed with other causes of VAP, such as Staphylococcus aureus and Escherichia coli (2, 3). These observations provided a scientific rationale for current American Thoracic Society/Infectious Diseases Society of America guidelines recommending that VAP caused by P. aeruginosa be treated with longer courses of antibiotics than VAP caused by many other bacterial pathogens (4). But what is the mechanism responsible for the persistence of P. aeruginosa? In this issue of the Journal (pp. 513–519), El Solh and colleagues add an important piece to the puzzle of P. aeruginosa persistence in VAP (5). Their findings suggest that type III secretion plays a major role in this aspect of infection. The P. aeruginosa type III secretion system is a complex syringe-like apparatus on the bacterial surface that injects proteins (called effector proteins) directly into host cells (6). Two effector proteins, ExoU and ExoS, are particularly virulent in animal models of acute pneumonia (7). Importantly, VAP isolates of P. aeruginosa differ in the complement of type III effector proteins they secrete, with some strains lacking functional type III secretion systems altogether (8, 9). El Solh and colleagues performed noninvasive bronchoscopy on 34 patients with VAP caused by P. aeruginosa. All patients received antimicrobial therapy to which their isolates were initially susceptible. Despite this, in 13 of 24 patients infected with type III secretion–positive strains, P. aeruginosa was recovered from the lungs after 8 days of therapy. In contrast, P. aeruginosa did not persist in the lungs of any of the 10 patients infected with type III secretion–negative strains. Persistence appeared to be clinically significant in that relapse occurred in 8 of 13 patients with P. aeruginosa still present in their lungs at the completion of antimicrobial therapy. Also, the survival rate for patients infected with nonsecreting strains was 66%, compared with only 32% in patients infected with secreting strains. These findings are intriguing and suggest that type III secretion may be acting in a way that allows bacterial persistence in the harsh pulmonary environment consisting of immune responses and antibiotics; this persistence may account for previous reports that type III secretion is associated with poor outcomes in P. aeruginosa acute respiratory infections (8, 9). How might functional type III secretion lead to bacterial persistence in the lungs? One possibility is that in vivo induction of type III secretion decreases susceptibility to antimicrobial agents. In this regard, it is interesting that ExoU+ strains have been reported to be more resistant to certain antibiotics than other strains (10). El Solh and colleagues, however, provide evidence supporting another explanation: type III secretion targets neutrophils, rendering this important component of the immune system less capable of eradicating P. aeruginosa. Secretion of type III toxins was associated with apoptotic changes in neutrophils and increased release of neutrophil elastase in the lungs. These in vivo results fit well with earlier in vitro observations demonstrating that type III secretion causes apoptosis and death of neutrophils and macrophages (11–14). Thus, type III secretion may tilt the precarious balance between the host immune response (aided by antimicrobial therapy) and bacterial survival mechanisms in favor of the bacterium. If this is indeed the case, immunotherapies that block type III secretion may prove useful adjuncts in the treatment of pneumonia caused by P. aeruginosa (15). Although intriguing, the current study has several limitations. It consists of a relatively small number of patients from a single site. Larger studies involving multiple sites will be necessary to determine whether these findings are generalizable. Patients infected with type III secretion–positive strains tended to have poorer APACHE II scores at baseline, suggesting that comorbid conditions contributed to their inability to clear P. aeruginosa from their lungs. Finally, it is unclear whether the observed increased level of apoptosis in neutrophils was the cause or the result of enhanced bacterial persistence. Pneumonia itself influences levels of apoptosis within the lungs (16), and P. aeruginosa has multiple mechanisms by which it causes apoptosis. Therefore, increased apoptosis may merely be a marker for the continued presence of large numbers of bacteria rather than an immune insult that allows such persistence. Nevertheless, the findings of El Solh and colleagues are intriguing and warrant further consideration. It is said that good research asks two new questions for every one answered, and this work is no exception. Further study is necessary to more clearly define the host cell types injected with type III toxins in vivo and the mechanisms by which these cells are incapacitated. In meningitis, bactericidal antibiotics are sufficient to eradicate bacteria with minimal assistance from the host immune system. Why do they not do so in pneumonia caused by P. aeruginosa? Until these questions are answered, P. aeruginosa will remain an uninvited guest that refuses to leave. FOOTNOTES Conflict of Interest Statement: A.R.H. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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