Collaboration between macrophages and vaccine-induced CD4+ T cells confers protection against lethal Pseudomonas aeruginosa pneumonia during neutropenia
Channing Laboratory, Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.The Journal of Infectious Diseases (Impact Factor: 6). 10/2012; 207(1). DOI: 10.1093/infdis/jis657
The utility of vaccine-based strategies to prevent lethal bacterial infection in a host with neutropenia is not well defined. Here, we show in a neutropenic mouse model that immunity induced by mucosal vaccination with a live-attenuated P. aeruginosa vaccine is protective against lethal P. aeruginosa pneumonia caused by both vaccine-homologous and -heterologous strains, whereas passive immunization confers only vaccine-homologous protection. Cells in the macrophage-lineage served as crucial innate cellular effectors in the neutropenic host after active immunization. Vaccine efficacy was CD4 T cell-dependent and associated with post-infectious accumulation of macrophage-lineage cells in the alveolar space as well as enhanced P. aeruginosa clearance from the lung. Adaptive CD4 T cells produced GM-CSF upon re-stimulation in vitro, and local GM-CSF was critical for vaccine efficacy. Thus, collaboration between the innate and adaptive effectors induced by mucosal vaccination can overcome neutropenia and confer protection against lethal bacterial infection in the profoundly neutropenic host.
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ABSTRACT: Despite the high prevalence of antimicrobial resistance among Pseudomonas aeruginosa bacteremia, the clinical consequence of resistance remains unclear. The purpose of this study was to identify predictors of mortality and evaluate the clinical impact of antimicrobial resistance on outcome in P. aeruginosa bacteremia. A retrospective cohort study including patients with P. aeruginosa bacteremia was performed. The risk factors for antimicrobial resistances were evaluated, and the impact of the respective resistances on mortality was assessed. Of 202 P. aeruginosa bacteremia cases, the resistance rates to ceftazidime, piperacillin, imipenem, fluoroquinolone, and aminoglycoside were 36.6%, 22.3%, 22.8%, 23.8%, and 17.8%, respectively. A prior use of fluoroquinolones and an indwelling urinary catheter were common risk factors for all types of antimicrobial resistance. The overall 30-day mortality rate was 25.2% (51/202), and the risk factors for mortality were corticosteroid use, nosocomial acquisition, polymicrobial infection, an increasing Charlson's weighted co-morbidity index, and intensive care unit care (p < 0.05). As compared with the susceptible group, ceftazidime-, piperacillin-, or imipenem-resistant groups had a higher mortality (p < 0.05). A multivariate analysis showed that resistance to ceftazidime or imipenem remained a significant factor associated with mortality (odds ratio, 2.96; 95% confidential interval, 1.20-7.31; and odds ratio, 2.74; 95% confidential interval, 1.02-7.31, respectively). Antimicrobial resistance, especially to ceftazidime or imipenem, adversely affected outcome in patients with P. aeruginosa bacteremia.Microbial drug resistance (Larchmont, N.Y.) 03/2011; 17(2):305-12. DOI:10.1089/mdr.2010.0170 · 2.49 Impact Factor
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ABSTRACT: Purpose of review: Pulmonary infections are particularly common in the immunosuppressed host. This review discusses emerging threats, newer modalities of diagnostic tests and emerging treatment options, and also highlights the increasing problem of antimicrobial resistance. Recent findings: Nosocomial pneumonia is increasingly due to multidrug-resistant Gram-negative organisms in immunosuppressed patients. Viral pneumonias remain a very significant threat, present atypically and carry a high mortality. Aspergillosis remains the most common fungal infection, and infections due to Mucorales are increasing. Multidrug-resistant tuberculosis is on the increase throughout the world. Mixed infections are common and early bronchoscopy with appropriate microbiological tests, including molecular diagnostics, optimise management and reduce mortality. Conclusion: Pulmonary infection remains the most frequent infectious complication in the immunocompromised host. These complex infections are often mixed, have atypical presentations and can be due to multidrug-resistant organisms. Multidisciplinary involvement in specialist centres with appropriate diagnostics, treatment and infection control improves outcome. There is a desperate need for new antimicrobial agents active against Gram-negative pathogens.Current opinion in pulmonary medicine 03/2013; 19(3). DOI:10.1097/MCP.0b013e32835f82a9 · 2.76 Impact Factor
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ABSTRACT: Pseudomonas aeruginosa is an opportunistic pathogen that causes acute and chronic infections in humans. Pyocins are bacteriocins produced by P. aeruginosa that are usually released through lysis of the producer strains. Expression of pyocin genes is negatively regulated by PrtR which gets cleaved under SOS response, leading to up regulation of pyocin synthetic genes. Previously, we demonstrated that PrtR is required for the expression of type III secretion system (T3SS), which is an important virulence component of P. aeruginosa. In this study, we demonstrate that mutation in prtR results in reduced bacterial colonization in a mouse acute pneumonia model. Examination of bacterial and host cells in the bronchoalveolar lavage fluids from infected mice revealed that expression of PrtR is induced by reactive oxygen species (ROS) released by neutrophils. We further demonstrate that treatment with hydrogen peroxide or ciprofloxacin, known to induce SOS response and pyocin production, resulted in elevated PrtR mRNA level. Overexpression of PrtR by a tac promoter repressed the endogenous prtR promoter activity and electrophoretic mobility shift assay revealed that PrtR binds to its own promoter, suggesting an autorepressive mechanism of regulation. High level of PrtR expressed from a plasmid resulted in increased T3SS gene expression during infection and higher resistance against ciprofloxacin. Overall, our results suggest that the autorepression of PrtR contributes to the maintenance of relatively stable level of PrtR, which is permissive to T3SS gene expression in the presence of ROS while increasing bacterial tolerance to stresses, such as ciprofloxacin, by limiting pyocin production.Infection and immunity 02/2014; 82(4). DOI:10.1128/IAI.01388-13 · 3.73 Impact Factor
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