Viral suppressors of the RIG-I-mediated interferon response are pre-packaged in influenza virions

Nat Commun. 2014 Dec 9:5:5645. doi: 10.1038/ncomms6645.

Abstract

The type I interferon (IFN) response represents the first line of defence to invading pathogens. Internalized viral ribonucleoproteins (vRNPs) of negative-strand RNA viruses induce an early IFN response by interacting with retinoic acid inducible gene I (RIG-I) and its recruitment to mitochondria. Here we employ three-dimensional stochastic optical reconstruction microscopy (STORM) to visualize incoming influenza A virus (IAV) vRNPs as helical-like structures associated with mitochondria. Unexpectedly, an early IFN induction in response to vRNPs is not detected. A distinct amino-acid motif in the viral polymerases, PB1/PA, suppresses early IFN induction. Mutation of this motif leads to reduced pathogenicity in vivo, whereas restoration increases it. Evolutionary dynamics in these sequences suggest that completion of the motif, combined with viral reassortment can contribute to pandemic risks. In summary, inhibition of the immediate anti-viral response is 'pre-packaged' in IAV in the sequences of vRNP-associated polymerase proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cell Line, Tumor
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / chemistry*
  • Evolution, Molecular
  • Female
  • Humans
  • Imaging, Three-Dimensional
  • Influenza A virus / pathogenicity*
  • Interferon Type I / immunology*
  • Lung / immunology
  • Lung / virology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mitochondria / virology*
  • RNA Viruses / pathogenicity
  • Receptors, Immunologic
  • Viral Load
  • Viral Proteins / chemistry
  • Virion / chemistry*
  • Virulence

Substances

  • Interferon Type I
  • Receptors, Immunologic
  • Viral Proteins
  • influenza virus polymerase basic protein 1
  • RIGI protein, human
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases