PKR-mediated Stress Response Enhances Dengue and Zika Virus Replication

Abstract

The mechanisms by which flaviviruses use non-canonical translation to support their replication in host cells are largely unknown. Here we investigated how the integrated stress response (ISR), which promotes translational arrest by eIF2[a] phosphorylation (p-eIF2[a]), regulates flavivirus replication. During Dengue virus (DENV) and Zika virus (ZIKV) infection, eIF2[a] phosphorylation peaked at 24 hours post infection and was dependent on PKR but not type I interferon. The ISR is activated downstream of p-eIF2 during infection with either virus, but translation arrest only occurred following DENV4 infection. Despite this difference, both DENV4 and ZIKV replication was impaired in cells lacking PKR, independent of IFN-I/NF-kB signalling or cell viability. By using a ZIKV 5' UTR reporter system as a model, we found that this region of the genome is sufficient to promote an enhancement of viral mRNA translation in the presence of an active ISR. Together we provide evidence that flaviviruses escape ISR translational arrest and co-opt this response to increase viral replication.