PLoS Pathogens | |
Type I IFN Triggers RIG-I/TLR3/NLRP3-dependent Inflammasome Activation in Influenza A Virus Infected Cells | |
Julien Pothlichet1  Silvia M. Vidal2  Emil Skamene2  Jenny P-Y. Ting3  Beckley K. Davis4  Veronika von Messling5  Isabelle Meunier6  | |
[1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada;Department of Microbiology and Immunology School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America;INRS-Institut Armand-Frappier, Laval, Quebec, Canada;Institut Pasteur, Centre François Jacob, Paris, France;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America;McGill Centre for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada | |
关键词: Influenza A virus; Epithelial cells; Small interfering RNAs; Inflammasomes; Secretion; Ferrets; Immunoblotting; Interferons; | |
DOI : 10.1371/journal.ppat.1003256 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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.
【 授权许可】
CC BY
【 预 览 】
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