Species-specific inhibition of capripoxvirus replication by host antiviral protein kinase R

The role of interferon (IFN)-induced protein kinase R (PKR) in capripoxvirus (CaPV)-infected cells remains unknown. In this study, we show that CaPV infection triggered PKR and eukaryotic translation initiation factor 2 alpha (eIF2α) protein phosphorylation in a dose-dependent manner, and that this leads to decreased CaPV replication. Overexpression of PKR compromised viral gene expression and inhibited sheeppox virus (SPPV) replication. Downregulation of PKR with siRNAs significantly decreased eIF2α phosphorylation and reduced the mRNA level of IFN-β, which increased virus replication. In luciferase assays, species-different CaPVs K3L proteins inhibited sheep PKR (sPKR): goatpox virus K3L strongly inhibited sPKR and goat PKR (gPKR), but SPPV K3L only partially inhibited gPKR. These results are the first to show that SPPV infection induces phosphorylation of eIF2α through PKR activation, which then results in restriction of CaPV replication. Furthermore, our data show that CaPV K3L inhibits PKR in a species-specific manner. The results presented are consistent with the hypothesis that different levels of PKR inhibition by K3L orthologs from various viruses could potentially contribute to the host range function of K3L.