Activation of PKR by Bunyamwera virus is independent of the viral interferon antagonist NSs

Hein Streitenfeld, Amanda Boyd, John K Fazakerley, Anne Bridgen, Richard M Elliott, Friedemann Weber

Research output: Contribution to journalArticlepeer-review

Abstract

Double-stranded RNA (dsRNA) is a by-product of viral RNA polymerase activity, and its recognition is one mechanism by which the innate immune system is activated. Cellular responses to dsRNA include induction of alpha/beta interferon (IFN) synthesis and activation of the enzyme PKR, which exerts its antiviral effect by phosphorylating the eukaryotic initiation factor eIF-2 alpha, thereby inhibiting translation. We have recently identified the nonstructural protein NSs of Bunyamwera virus (BUNV), the prototype of the family Bunyaviridae, as a virulence factor that blocks the induction of IFN by dsRNA. Here, we investigated the potential of NSs to inhibit PKR. We show that wild-type (wt) BUNV that expresses NSs triggered PKR-dependent phosphorylation of eIF-2 alpha to levels similar to those of a recombinant virus that does not express NSs (BUNdelNSs virus). Furthermore, the sensitivity of viruses in cell culture to IFN was independent of PKR and was not determined by NSs. PKR knockout mice, however, succumbed to infection approximately 1 day earlier than wt mice or mice deficient in expression of RNase L, another dsRNA-activated antiviral enzyme. Our data indicate that (i) bunyaviruses activate PKR, but are only marginally sensitive to its antiviral effect, and (ii) NSs is different from other IFN antagonists, since it inhibits dsRNA-dependent IFN induction but has no effect on the dsRNA-activated PKR and RNase L systems.
Original languageEnglish
Pages (from-to)5507-11
Number of pages5
JournalJournal of Virology
Volume77
Issue number9
Publication statusPublished - May 2003

Keywords

  • Animals
  • Bunyamwera virus
  • Bunyaviridae Infections
  • Cells, Cultured
  • Cercopithecus aethiops
  • DNA-Binding Proteins
  • Enzyme Activation
  • Interferons
  • Mice
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Transcription Factors
  • Vero Cells
  • Viral Nonstructural Proteins
  • Virulence

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