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Encephalomyocarditis virus induces PKR-independent mitogen-activated protein kinase activation in macrophages

Jason M Moran1, Michael A Moxley, R Mark L Buller

  • 1Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1402 South Grand Boulevard, Saint Louis, MO 63104, USA.

Journal of Virology
|July 30, 2005
PubMed

Insights

The double-stranded RNA-dependent protein kinase (PKR) is not essential for virus-induced inflammatory responses in macrophages. Macrophage activation and inflammatory gene expression during viral infection are mediated by virion-host cell interactions, independent of PKR.

Area of Science:

  • Immunology
  • Virology
  • Cell Biology

Background:

  • The double-stranded RNA-dependent protein kinase (PKR) is a key mediator of antiviral responses.
  • The role of PKR in virus-induced inflammatory gene expression in macrophages remains incompletely understood.

Purpose of the Study:

  • To investigate the role of PKR in the induction of inducible nitric oxide synthase (iNOS) and the activation of signaling pathways during viral infection in macrophages.
  • To determine whether virion-host cell interactions contribute to PKR-independent macrophage activation.

Main Methods:

  • Utilized RAW264.7 cells and PKR+/+ and PKR-/- macrophages infected with encephalomyocarditis virus (EMCV).
  • Assessed iNOS expression, nitric oxide production, and activation of mitogen-activated protein kinase (MAPK), cyclic AMP response element binding protein (CREB), and nuclear factor kappaB (NF-kappaB) signaling pathways.
  • Compared the effects of intact EMCV virions and empty EMCV capsids on macrophage activation.

Main Results:

  • EMCV infection induced iNOS expression and nitric oxide production in a PKR-independent manner.
  • EMCV infection activated MAPK, CREB, and NF-kappaB signaling pathways in both PKR+/+ and PKR-/- macrophages.
  • Activation of these pathways did not correlate with PKR activity or viral RNA accumulation.
  • Empty EMCV capsids induced iNOS expression, nitrite production, and signaling pathway activation comparable to intact virions.

Conclusions:

  • PKR is not required for virus-induced iNOS expression or the activation of key signaling pathways in macrophages.
  • Virion-host cell interactions, potentially through structural components of the virus, are primary mediators of PKR-independent macrophage activation.
  • These findings elucidate a novel mechanism in the macrophage antiviral response involving inflammatory gene expression.

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