Influenza virus activates inflammasomes through intracellular M2 channel

Influenza virus, a negative stranded RNA virus causing severe illness in humans and animals, stimulates the inflammasome through the NOD-like receptor (NLR), NLRP3. However, the mechanism by which influenza virus activates the NLRP3 inflammasome is unknown. Here, we show that the influenza virus M2 protein, a proton-selective ion channel important in viral pathogenesis, stimulates the NLRP3 inflammasome pathway. M2 channel activity was required for influenza activation of inflammasomes, and was sufficient to activate inflammasomes in primed macrophages and dendritic cells. M2-induced inflammasome activation required its localization to Golgi and was dependent on pH gradient. Our results reveal a mechanism by which influenza virus infection activates inflammasomes, and identifies the sensing of disturbances in intracellular ionic concentrations as a novel pathogen recognition pathway.