Key result
Encephalomyocarditis virus infection induces iNOS expression, nitric oxide production, and activation of MAP kinases, CREB, and NF-κB in macrophages through a PKR-independent mechanism.
Virion-host cell interactions, rather than viral replication or PKR activation, are primary mediators of the early macrophage antiviral response and inflammatory gene expression.
Suggests virion-host interactions drive early macrophage inflammation in EMCV; hypothesis-generating for PKR-independent pathways in viral disease models.
In this study, we provide evidence that the double-stranded RNA-dependent protein kinase (PKR) is not required for virus-induced expression of inducible nitric oxide synthase (iNOS) or the activation of specific signaling pathways in macrophages. The infection of RAW264.7 cells with encephalomyocarditis virus (EMCV) induces iNOS expression and nitric oxide production, which are unaffected by a dominant-negative mutant of PKR. EMCV infection also activates the mitogen-activated protein kinase, cyclic AMP response element binding protein, and nuclear factor kappaB (NF-kappaB) signaling cascades at 15 to 30 min postinfection in PKR+/+ and PKR-/- macrophages. Activation of these signaling cascades does not temporally correlate with PKR activity or the accumulation of EMCV RNA, suggesting that an interaction between a structural component of the virion and the cell surface may activate macrophages. Consistent with this hypothesis, empty EMCV capsids induced comparable levels of iNOS expression, nitrite production, and activation of these signaling cascades to those induced by intact virions. These findings support the hypothesis that virion-host cell interactions are primary mediators of the PKR-independent activation of signaling pathways that participate in the macrophage antiviral response of inflammatory gene expression.
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Moran et al. (2005) studied Encephalomyocarditis Virus infection. Encephalomyocarditis Virus (EMCV) infection vs. Uninfected cells or PKR-deficient cells was evaluated on iNOS expression, nitric oxide production, and activation of MAP kinases, CREB, and NF-κB. Encephalomyocarditis virus infection induces iNOS expression, nitric oxide production, and activation of MAP kinases, CREB, and NF-κB in macrophages through a PKR-independent mechanism.
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