Disruption of Erk-dependent Type I Interferon Induction Breaks the Myxoma Virus Species Barrier

Nat Immunol. 2004 Dec;5(12):1266-74. doi: 10.1038/ni1132. Epub 2004 Oct 24.

Abstract

Myxoma virus, a member of the poxvirus family, causes lethal infection only in rabbits, but the mechanism underlying the strict myxoma virus species barrier is not known. Here we show that myxoma virus infection of primary mouse embryo fibroblasts elicited extracellular signal-regulated kinase (Erk) signaling, which was integrated to interferon regulatory factor 3 activation and type I interferon induction. We further show that Erk inactivation or disruption of interferon signaling mediated by the transcription factor STAT1 broke the cellular blockade to myxoma virus multiplication. Moreover, STAT1 deficiency rendered mice highly susceptible to lethal myxoma virus infection. Thus, the Erk-interferon-STAT1 signaling cascade elicited by myxoma virus in nonpermissive primary mouse embryo fibroblasts mediates an innate cellular barrier to poxvirus infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Eukaryotic Initiation Factor-2 / metabolism
  • Interferon Regulatory Factor-3
  • Interferon Type I / biosynthesis*
  • Interferon Type I / immunology
  • MAP Kinase Signaling System* / drug effects
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / deficiency
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myxoma virus / immunology
  • Myxoma virus / physiology*
  • Phosphorylation
  • Poxviridae Infections / immunology*
  • Poxviridae Infections / metabolism
  • Poxviridae Infections / virology*
  • STAT1 Transcription Factor
  • Species Specificity
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • eIF-2 Kinase / metabolism

Substances

  • DNA-Binding Proteins
  • Eukaryotic Initiation Factor-2
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Irf3 protein, mouse
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • Transcription Factors
  • eIF-2 Kinase
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases