Pseudomonas aeruginosa reduces the immune response to respiratory viruses (99.33)

Abstract

Abstract P. aeruginosa chronically colonizes the respiratory tract of patients with chronic obstructive pulmonary disease, bronchiectasis and Cystic Fibrosis. These patients experience debilitating and life-threatening viral exacerbations of unknown etiology. Cif, a bacterial toxin secreted by P. aeruginosa, promotes the degradation of several ABC transporters involved in innate immunity, including CFTR and Pgp. The current study tests the hypothesis that Cif enhances the degradation of the transporter associated with antigen processing (TAP), resulting in reduced adaptive T-cell responses to viral pathogens. Cif inhibited the deubiquitinating enzyme, ubiquitin specific protease 10 (USP10), resulting in a time-dependent increase in the polyubiquitination and proteasomal degradation of TAP1. Cif inhibited USP10 activity by stabilizing an inhibitory protein-protein interaction between USP10 and G3BP1. The Cif-mediated decrease in TAP1 expression resulted in decreased MHC class I viral antigen presentation, CD8+ cytotoxic T lymphocyte (CTL) recognition of influenza virus-infected cells and dramatically reduced MHC class I cell surface levels on CD11c+ cells in the BAL of mice treated with P. aeruginosa. We propose that P. aeruginosa, by secreting the Cif toxin, inhibits the ability of CTL to recognize and eliminate viral infections, severely compromising the immune defenses of the lung. This is the first identified bacterial toxin that inhibits the viral immune response of the host.