Alpha/beta interferon priming of dendritic cells significantly inhibited early cap-dependent translation of Sindbis virus genomes through a PKR/RNase L-independent mechanism requiring de novo gene transcription.
IFN-alpha/beta inhibits Sindbis virus translation through a novel PKR/RNase L-independent pathway targeting cap-dependent translation in dendritic cells.
The tropism of Sindbis virus (SB) for cells of the dendritic cell (DC) lineage and the virulence of SB in vivo are largely determined by the efficacy of alpha/beta interferon (IFN-alpha/beta)-mediated antiviral responses. These responses are essentially intact in the absence of PKR and/or RNase L (K. D. Ryman, L. J. White, R. E. Johnston, and W. B. Klimstra, Viral Immunol. 15:53-76, 2002). In the present studies, we investigated the nature of antiviral effects and identity of antiviral effectors primed by IFN-alpha/beta treatment of bone marrow-derived DCs (BMDCs) generated from mice deficient in PKR and RNase L (TD). IFN-alpha/beta priming exerted significant antiviral activity at very early stages of SB replication and most likely inhibited the initial translation of infecting genomes. The early effect targeted cap-dependent translation as protein synthesis from an SB-like and a simple RNA were inhibited by interferon treatment, but an encephalomyocarditis virus internal ribosome entry site-driven element exhibited no inhibition. Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 was defective after virus infection of TD cells, suggesting other mechanisms of translation inhibition. To identify components of these alternative antiviral pathway(s), we have compared global gene regulation in BMDCs derived from normal 129 Sv/Ev, IFNAR1-/-, and TD mice following infection with SB or treatment with IFN-alpha/beta. Candidate effectors of alternative antiviral pathways were those genes induced by virus infection or IFN-alpha/beta treatment in 129 Sv/Ev and TD-derived BMDC but not in virus-infected or IFN-alpha/beta-treated IFNAR1-/- cells. Statistical analyses of gene array data identified 44 genes that met these criteria which are discussed.
Ryman et al. (Thu,) conducted a other in Sindbis virus infection. Alpha/Beta Interferon (IFN-α/β) priming vs. Untreated cells was evaluated on Sindbis virus translation and replication (measured by luciferase activity and viral protein synthesis). Alpha/beta interferon priming of dendritic cells significantly inhibited early cap-dependent translation of Sindbis virus genomes through a PKR/RNase L-independent mechanism requiring de novo gene transcription.