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

PLoS Pathog. 2013;9(4):e1003256. doi: 10.1371/journal.ppat.1003256. Epub 2013 Apr 11.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Epithelial Cells / metabolism
  • Ferrets
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism*
  • Influenza A Virus, H1N1 Subtype* / metabolism
  • Interferon-beta / metabolism*
  • Lung / metabolism
  • Lung / virology
  • Macrophages / immunology
  • Male
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • RNA Interference
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / immunology
  • Signal Transduction
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism*
  • Transcription Factors / metabolism
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / metabolism
  • Viral Nonstructural Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • INS1 protein, influenza virus
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Transcription Factors
  • Tripartite Motif Proteins
  • VISA protein, human
  • Viral Nonstructural Proteins
  • Interferon-beta
  • TRIM25 protein, human
  • Ubiquitin-Protein Ligases
  • Caspase 1
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases