Uncovering the role of resident memory T cell in chronic lung disease viral infections

About This Grant

PROJECT SUMMARY Respiratory viral infections contribute to chronic lung disease, such as chronic obstructive pulmonary disease (COPD), pathogenesis. Although cigarette smoke (CS) exposure is the cardinal risk factor for development of COPD, repeated infections contribute to persistent inflammation and worsening of the disease. However, the underlying cellular and molecular mechanisms that predispose COPD patients to recurrent viral infections and ongoing inflammation have not been elucidated. In the lung, TRM cells, defined in this proposal as CD8+, CD49a+ or CD69+, and/or CD103+ T cells, provide long-lasting local protective immunity and facilitate rapid intracellular pathogen elimination upon secondary infection. Yet, a role for lung TRM cells in COPD recurrent viral infections has never been studied. Our lab has established a protective role for fatty-acid binding protein 5 (FABP5) in COPD pathogenesis. In this proposal, we focus on regulation of lung TRM function by FABP5 as a novel pathway mediating increased susceptibility to recurrent infections in COPD. We hypothesize that reduction of TRM cells in COPD lungs predisposes to recurrent influenza virus infections. In addition, we also propose that the reduced TRM cell number is due to downregulation of FABP5 expression and impaired mitochondrial metabolism. Specifically, we propose to examine if 1) impaired TRM cell response contributes to increased susceptibility to influenza virus infection in COPD using CS-exposed and TRM cell depletion murine models and 2) FABP5 is sufficient for TRM metabolic survival and function in a murine model of COPD viral infection. This work has the potential to uncover novel cell types and signaling pathways for therapeutic targeting to mitigate increased susceptibility to recurrent infections in COPD and potentially slow the progression of this currently incurable disease.