Inflammatory response of mast cells during influenza A virus infection is mediated by active infection and RIG-I signaling

摘要

Influenza A virus (IAV) is a major respiratory pathogen of both humans and animals. The lung is protected from pathogens by alveolar epithelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. The role of alveolar epithelial cells, endothelial cells, and alveolar macrophages during IAV infection has been previously studied. Here we address the role of mast cells during IAV infection. Respiratory infection with A/WSN/33 causes significant disease and immunopathology in C57BL/6 mice, but not B6.Cg-Kit^W-sh mice that lack mast cells. During in vitro co-culture, A/WSN/33 caused mast cells to release histamine, secrete cytokines and chemokines, and produce leukotrienes. Moreover, when mast cells were infected with IAV, the virus did not replicate within mast cells. Importantly, human H1N1, H3N2, and influenza B virus isolates could also activate mast cells in vitro. Mast cell production of cytokines and chemokines occurs in a RIG-I/MAVS-dependent mechanism; in contrast, histamine production occurred through a RIG-I/MAVS-independent mechanism. Our data highlight that following IAV infection the response of mast cells is controlled by multiple receptors. In conclusion, we have identified a unique inflammatory cascade activated during IAV infection that could potentially be targeted to limit morbidity following IAV infection.