PKR's Protective Role in Viral Myocarditis

Virology. 2003 Sep 15;314(1):92-100. doi: 10.1016/s0042-6822(03)00414-8.

Abstract

Reovirus-induced murine myocarditis provides an excellent model for the human disease. Previously, we showed that reovirus induction of and sensitivity to interferon-beta (IFN-beta) are important determinants of protection against cardiac damage. IFN-beta induces a number of genes with antiviral activities, including the dsRNA-activated protein kinase, PKR. Once bound to viral dsRNA, PKR becomes activated and phosphorylates eukaryotic initiation factor-2 alpha (eIF2 alpha) leading to the cessation of host cell translation. Additionally, activated PKR can exert its antiviral effects by inducing phosphorylation of I kappa B, leading to the activation of the transcription factor NF kappa B and subsequent induction of IFN-beta. Thus, activated PKR can both induce and be induced by IFN-beta. Recently, numerous reports have shown PKR to be dispensable for both induction of IFN as well as protection against disease. However, both PKR's role in the heart in response to viral infection and its ability to prevent cardiac damage have gone largely unexplored. Here, we demonstrate PKR to be critical for viral induction of IFN-beta in primary cardiac myocyte cultures. Additionally, we show that loss of PKR leads to an increase in virulence for both myocarditic and nonmyocarditic reoviruses. Finally, we demonstrate PKR to be critical for protection against reovirus-induced viral myocarditis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Activation
  • Humans
  • Interferon-beta / biosynthesis*
  • Mice
  • Mice, Inbred C57BL
  • Myocarditis / immunology*
  • Myocarditis / virology
  • Myocardium / cytology
  • Orthoreovirus / pathogenicity*
  • Reoviridae Infections / immunology*
  • Reoviridae Infections / virology
  • Transfection
  • eIF-2 Kinase / metabolism*

Substances

  • Interferon-beta
  • eIF-2 Kinase