Influenza A Virus NS1 Protein Inhibits the NLRP3 Inflammasome

PLoS One. 2015 May 15;10(5):e0126456. doi: 10.1371/journal.pone.0126456. eCollection 2015.

Abstract

The inflammasome is a molecular platform that stimulates the activation of caspase-1 and the processing of pro-interleukin (IL)-1β and pro-IL-18 for secretion. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) protein is activated by diverse molecules and pathogens, leading to the formation of the NLRP3 inflammasome. Recent studies showed that the NLRP3 inflammasome mediates innate immunity against influenza A virus (IAV) infection. In this study, we investigated the function of the IAV non-structural protein 1 (NS1) in the modulation of NLRP3 inflammasome. We found that NS1 proteins derived from both highly pathogenic and low pathogenic strains efficiently decreased secretion of IL-1β and IL-18 from THP-1 cells treated with LPS and ATP. NS1 overexpression significantly impaired the transcription of proinflammatory cytokines by inhibiting transactivation of the nuclear factor-κB (NF-κB), a major transcription activator. Furthermore, NS1 physically interacted with endogenous NLRP3 and activation of the NLRP3 inflammasome was abrogated in NS1-expressing THP-1 cells. These findings suggest that NS1 downregulates NLRP3 inflammasome activation by targeting NLRP3 as well as NF-κB, leading to a reduction in the levels of inflammatory cytokines as a viral immune evasion strategy.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Blotting, Western
  • Carrier Proteins / metabolism*
  • Cell Line
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Humans
  • Immunoprecipitation
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism*
  • Influenza A virus / metabolism*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / pharmacology
  • Microscopy, Confocal
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Real-Time Polymerase Chain Reaction
  • Viral Nonstructural Proteins / metabolism*

Substances

  • Carrier Proteins
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Lipopolysaccharides
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Viral Nonstructural Proteins
  • Adenosine Triphosphate