The Pseudomonas aeruginosa toxin Cif reduces MHC class I antigen presentation and viral immunity (131.4)

Abstract

Abstract Pseudomonas aeruginosa is an opportunistic pathogen critical to the pathogenesis of nosocomial infections, chronic obstructive pulmonary disease, ventilator-associated pneumonia, bronchiectasis and Cystic Fibrosis. Patients chronically infected with P. aeruginosa often experience debilitating viral exacerbations, the cause of which is unknown. Previously, we demonstrated that Cif, a bacterial toxin secreted by P. aeruginosa, promotes the degradation of several ABC transporters involved in innate immunity and the drug bioavailability, including CFTR and Pgp. The current study was conducted to test the hypothesis that Cif enhances the degradation of the transporter associated with antigen processing (TAP) in airway epithelial cells, resulting in reduced class I MHC antigen presentation and therefore, diminished immune responses to viral pathogens. Cif inhibited the deubiquitinating enzyme, ubiquitin specific protease 10, resulting in a time-dependent increase in the polyubiquitination and proteosomal degradation of TAP1. The Cif-mediated decrease in TAP1 expression resulted in a decrease in class I MHC expression at the plasma membrane. Furthermore, Cif decreased MHC class I antigen presentation and cytotoxic T lymphocyte (CTL) recognition of influenza virus antigen, as measured by TNF-α secretion, in a time-dependent manner. These observations suggest that P. aeruginosa, by secreting Cif, inhibits the ability of CTL to eliminate viral infections, severely compromising the immune defenses of the lung.