Infection and activation of mast cells by influenza A virus enhances viral-induced pathology (P6030)

Abstract

Abstract Influenza A virus (IAV) is a seasonal respiratory pathogen that can result in severe lung pathology. The role of mast cells has been under explored during severe pulmonary viral infections. We found that both A/WSN/33 (WSN) and A/PR/8/34 (PR8) influenza viruses cause significant immunopathology in C57BL/6 mice, but only WSN induced pathology was mast cell dependent. Using in vitro-derived bone marrow cultured mast cells (BMCMC), we found that WSN, but not PR8, directly activated BMCMC to produce histamine, leukotrienes, inflammatory cytokines, and anti-viral chemokines. Moreover, human H1N1, H3N2, and influenza B virus isolates could activate both murine BMCMC and the human mast cell line HMC-1 in vitro. BMCMC activation required infection of mast cells by IAV, which was dependent on the viral hemagglutinin. Cytokine and chemokine production from BMCMC occurs in a RIG-I/MAVS-dependent fashion which required the de novo production of vRNA; conversely, degranulation occurs through a RIG-I/MAVS-independent mechanism. Reconstitution of mast cell deficient mice with RIG-I-/- BMCMC generated lung pathology similar to wild type BMCMC, suggesting that mast cell degranulation, rather than production of cytokines, causes WSN induced lung pathology. Thus, we have identified a unique inflammatory cascade which could be therapeutically targeted to limit morbidity following infection with influenza virus.