Type I IFN Triggers RIG-I/TLR3/NLRP3-dependent Inflammasome Activation in Influenza A Virus Infected Cells

Influenza a virus (iav) triggers a contagious and potentially lethal respiratory disease. a protective il-1β response is mediated by innate receptors in macrophages and lung epithelial cells. nlrp3 is crucial in macrophages; however,which sensors elicit il-1β secretion in lung epithelial cells remains undetermined. here,we describe for the first time the relative roles of the host innate receptors rig-i (ddx58),tlr3,and nlrp3 in the il-1β response to iav in primary lung epithelial cells. to activate il-1β secretion,these cells employ partially redundant recognition mechanisms that differ from those described in macrophages. rig-i had the strongest effect through a mavs/trim25/riplet-dependent type i ifn signaling pathway upstream of tlr3 and nlrp3. notably,rig-i also activated the inflammasome through interaction with caspase 1 and asc in primary lung epithelial cells. thus,ns1,an influenza virulence factor that inhibits the rig-i/type i ifn pathway,strongly modulated the il-1β response in lung epithelial cells and in ferrets. the ns1 protein derived from a highly pathogenic strain resulted in increased interaction with rig-i and inhibited type i ifn and il-1β responses compared to the least pathogenic virus strains. these findings demonstrate that in iav-infected lung epithelial cells rig-i activates the inflammasome both directly and through a type i ifn positive feedback loop. © 2013 pothlichet et al.