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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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CARD Signaling Adaptor Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase 1 / genetics
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Caspase 1 / metabolism
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Cells, Cultured
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Cytoskeletal Proteins / metabolism
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DEAD Box Protein 58
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / metabolism*
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Epithelial Cells / metabolism
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Ferrets
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HEK293 Cells
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Humans
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Inflammasomes / metabolism*
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Influenza A Virus, H1N1 Subtype* / metabolism
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Interferon-beta / metabolism*
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Lung / metabolism
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Lung / virology
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Macrophages / immunology
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Male
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NLR Family, Pyrin Domain-Containing 3 Protein
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RNA Interference
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Receptors, Immunologic
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Respiratory Mucosa / cytology
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Respiratory Mucosa / immunology
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Signal Transduction
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Toll-Like Receptor 3 / genetics
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Toll-Like Receptor 3 / metabolism*
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Transcription Factors / metabolism
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Tripartite Motif Proteins
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Ubiquitin-Protein Ligases / metabolism
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Viral Nonstructural Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Cytoskeletal Proteins
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INS1 protein, influenza virus
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Inflammasomes
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MAVS protein, human
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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PYCARD protein, human
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Receptors, Immunologic
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TLR3 protein, human
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Toll-Like Receptor 3
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Transcription Factors
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Tripartite Motif Proteins
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Viral Nonstructural Proteins
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Interferon-beta
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TRIM25 protein, human
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Ubiquitin-Protein Ligases
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Caspase 1
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RIGI protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases