Viral priming of cell intrinsic innate antiviral signaling by the unfolded protein response

The innate response to a pathogen is critical in determining the outcome of the infection. However, the interplay of different cellular responses that are activated following viral infection and their contribution to innate antiviral signalling has not been clearly established. This work shows that flaviviruses, including Dengue, Zika, West Nile and Tick-borne encephalitis viruses, activate the unfolded protein response before transcription of interferon regulatory factor 3 induced genes. Infection in conditions of unfolded protein response priming leads to early activation of innate antiviral responses and cell intrinsic inhibition of viral replication, which is interferon regulatory factor 3 dependent. These results demonstrate that the unfolded protein response is not only a physiological reaction of the cell to viral infection, but also synergizes with pattern recognition sensing to mount a potent antiviral response. Innate immune responses are essential in the control of flavivirus infection. Here, the authors provide evidence that the unfolded protein response and the pattern recognition receptor pathways synergize to orchestrate innate antiviral responses and cell intrinsic inhibition of viral replication, a process mediated by IRF3.