Activation of mast cells by influenza A virus stimulates virus-induced immunopathology (HYP3P.353)

Abstract

Abstract Influenza A virus (IAV), a seasonal respiratory pathogen, results in severe lung pathology. Recent global analysis of lungs from mice infected with highly pathological IAV strains demonstrated enrichment of mast cells, but the role of mast cells during severe pulmonary viral infections has been under studied. We have recently shown that A/WSN/33 causes significant immunopathology in C57BL/6 mice and is mast cell-dependent. A/WSN/33(WSN) was able to directly activate mast cells to produce histamine, leukotrienes, inflammatory cytokines, and anti-viral chemokines. IAV-induced cytokine storm is thought to induce viral immunopathology, therefore we explored the importance of this response from mast cells. Mast cell cytokine production occurred in a RIG-I/MAVS-dependent fashion, but reconstitution of mast cell-deficient mice with RIG-I-/- mast cells generated lung pathology similar to wild type mast cells. Thus, it appears that mast cell degranulation rather than production of cytokines causes WSN-induced lung pathology. Mast cell degranulation occurs early in the viral entry cycle through a RIG-I/MAVS- and MyD88/Trif-independent mechanism. Using recombinant WSN strains, we found an association between the WSN hemaggultinin and neuraminidase proteins in the activation of mast cell degranulation and WSN-induced disease. We have identified a unique inflammatory cascade which could be therapeutically targeted to limit morbidity following infection with influenza virus.