Type I IFN triggers RIG-I/TLR3/NLRP3-dependent inflammasome activation in influenza A virus infected cells.

Authors:
Pothlichet J1, Meunier I, Davis BK, Ting JP, Skamene E, von Messling V, Vidal SM.
In:
Source: PLoS Pathog
Publication Date: (2013)
Issue: 4: e1003256.
Research Area:
Basic Research
Cells used in publication:
Epithelial, bronchial (NHBE), human
Species: human
Tissue Origin: lung
Abstract
Influenza A virus (IAV) triggers a contagious and potentially lethal respiratory disease. A protective IL-1ß response is mediated by innate receptors in macrophages and lung epithelial cells. NLRP3 is crucial in macrophages; however, which sensors elicit IL-1ß 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-1ß response to IAV in primary lung epithelial cells. To activate IL-1ß 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-1ß 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-1ß 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.