Type I IFN Triggers RIG-I/TLR3/NLRP3-dependent Inflammasome Activation in Influenza A Virus Infected Cells
Pothlichet J. Meunier I. Davis B.K. Ting J.P.-Y. Skamene E. von Messling V. Vidal S.M.
Pothlichet J.
Meunier I.
Davis B.K.
Ting J.P.-Y.
Skamene E.
Vidal S.M.
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Alternative Title
Abstract
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.
Keywords
cryopyrin, inflammasome, interferon, interleukin 1beta, interleukin 1beta converting enzyme, retinoic acid inducible protein I, small interfering RNA, toll like receptor 3, virulence factor, animal cell, animal experiment, article, controlled study, enzyme linked immunosorbent assay, ferret, gene silencing, human, human cell, immunoblotting, Influenza virus A, lung alveolus epithelium, macrophage, male, nonhuman, reverse transcription polymerase chain reaction, signal transduction, Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Caspase 1, Cells, Cultured, Cytoskeletal Proteins, DEAD-box RNA Helicases, Epithelial Cells, Ferrets, HEK293 Cells, Humans, Inflammasomes, Influenza A Virus, H1N1 Subtype, Interferon-beta, Lung, Macrophages, Male, Respiratory Mucosa, RNA Interference, Signal Transduction, Toll-Like Receptor 3, Transcription Factors, Ubiquitin-Protein Ligases, Viral Nonstructural Proteins, Influenza A virus, Mustela
Source Title
PLoS Pathogens
Publisher
Public Library of Science
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Date
2013
DOI
10.1371/journal.ppat.1003256
Type
Article