title: Type I IFN triggers RIG-I/TLR3/NLRP3-dependent inflammasome activation in influenza A virus infected cells.
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.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada. julien.pothlichet@pasteur.fr
authors.forename: Julien
authors.initials: J
authors.lastname: Pothlichet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.forename: Beckley K
authors.initials: BK
authors.lastname: Davis
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.forename: Emil
authors.initials: E
authors.lastname: Skamene
authors.forename: Veronika
authors.initials: V
authors.lastname: von Messling
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005289:Ferrets; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053118:Influenza A Virus, H1N1 Subtype / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000276:immunology; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D034622:RNA Interference; D011971:Receptors, Immunologic; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C085820:INS1 protein, influenza virus; D058847:Inflammasomes; C505371:MAVS protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta; C084523:TRIM25 protein, human; D044767:Ubiquitin-Protein Ligases; D020170:Caspase 1; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases