P58IPK, the cellular eIF2alpha kinase inhibitor, promotes viral mRNA translation and limits host death during influenza virus infection

Many viruses encode proteins that help them evade cellular viral defense mechanisms. Influenza virus also takes advantage of a cellular protein for the same purpose. P58IPK, a cellular inhibitor of the interferon-induced, double-stranded RNA-activated eIF2alpha kinase, PKR, is activated during influenza virus infection. P58IPK is also induced during ER stress and inhibits the ER-localized, elF2alpha kinase, PERK. The ability of P58IPK to interact with and inhibit multiple eIF2alpha kinases suggests it is a critical regulator of both cellular and viral mRNA translation.; We sought to define the role of P58IPK during influenza virus infection of mammalian cells. Using mouse embryo fibroblasts from P58 IPK -/- mice, we demonstrated that the absence of P58IPK lead to an increase in eIF2alpha phosphorylation and decreased influenza virus mRNA translation. In cells lacking the P58IPK target, PKR, the trends were reversed--elF2alpha phosphorylation was decreased and influenza virus mRNA translation was increased. Although P58IPK also inhibits PERK, the presence or absence of this kinase had little effect on influenza virus mRNA translation, despite reduced levels of eIF2alpha phosphorylation in cells lacking PERK. Taken together, our results support a model in which P58IPK regulates influenza virus mRNA translation and infection through a PKR-mediated mechanism which is independent of PERK.; Regarding the host during virus infection, a previous study showed that in plants lacking P58IPK, there was decreased viral replication but increased host death, suggesting that P58IPK modulates virulence. To this end, we examined influenza virus infection in P58 IPK -/- mice to determine if the trends would be similar to the plant system. During influenza virus infection, there was increased mortality in P58IPK -/- mice. At times early post-infection, there was decreased viral replication associated with a greater up-regulation of anti-viral and immune-related genes in the lungs of P58IPK -/- mice compared to wild-type controls. These mice also exhibited increased levels of apoptosis, suggesting a mechanism of increased death of the P58 IPK -/- mice. Together, these data are comparable to that in a virally-infected plant system in which P58IPK is required to promote viral replication and limit host death.