Polymicrobial Interactions in the Lung

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Pseudomonas aeruginosa is an opportunistic pathogen and an important pathogen in patients with chronic obstructive pulmonary disorder (COPD), community acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), non-CF bronchiectasis and cystic fibrosis (CF). Recent studies suggest that viral and P. aeruginosa infections of the lung are synergistic and dramatically contribute to the morbidity and mortality associated with COPD, CF, CAP, VAP, and non-CF bronchiectasis. The long-term goal of my research is to elucidate the cellular and molecular mechanisms whereby P. aeruginosa and respiratory viruses synergize to cause lung disease. My short-term research goal is to elucidate the mechanism whereby P. aeruginosa infection interferes with host clearance of respiratory virus. P. aeruginosa secretes a protein called Cif (CFTR Inhibitory Factor, originally named because of its ability to inhibit CFTR-mediated Cl secretion by airway cells), which is coded by the PA2934 (or cif) gene. Cif, which is secreted by laboratory and clinical isolates of P. aeruginosa, inhibits the host immune response by down-regulating CFTR Cl secretion and mucociliary clearance. In addition, Cif reduces the abundance of TAP1 (Transporter Associated with Antigen Processing), which my recent preliminary studies reveal, suppresses influenza A virus antigen presentation by class I MHC molecules and the ability of cytotoxic T lymphocytes (CTL) to clear viral infections. My preliminary data also demonstrate that cytokines, namely interferon-γ, released by the host in response to viral pathogens, increase the secretion of Cif from P. aeruginosa. Very little is known about how secreted bacterial proteins suppress the host immune response to viral pathogens, and there is minimal data elucidating how the host immune response alters the release of bacterial toxins from microbial pathogens. Accordingly, I will use in vitro biochemical, high resolution imaging, and in vivo immunological techniques to test the following four specific aims in this proposal: (1) Test the hypothesis that Cif reduces antigen presentation and CTL-mediated clearance; (2) Test the hypothesis that Cif reduces influenza virus antigen presentation and CTL-mediated clearance; (3) Test the hypothesis that P. aeruginosa and RSV co-infection benefits each pathogen by reducing viral antigen presentation and CTL-clearance of RSV and promoting P. aeruginosa colonization; and (4) Test the hypothesis that the host immune response increases virulence factor secretion by P. aeruginosa. I anticipate that these studies will elucidate how P. aeruginosa reduces the ability of the lung to clear viral infections and, ultimately, identify new therapeutic approaches to control combined P. aeruginosa and respiratory virus infections.