The cellular response to a pathogen is critical in determining the outcome of the infection and, as a consequence, viruses deploy a variety of strategies to subdue the antiviral signalling in order to achieve a productive infection.
More...The cellular response to a pathogen is critical in determining the outcome of the infection and, as a consequence, viruses deploy a variety of strategies to subdue the antiviral signalling in order to achieve a productive infection. Stress and innate responses are believed to synergise to contain virus replication efficiently. However, the kinetics of the different cellular responses to viral infection and their contribution to innate antiviral signalling has not been clearly established. Tick-borne encephalitis virus, which is a Flavivirus widely diffused in Central Europe, has been shown to efficiently delay the interferon response. Transcriptome analysis of tick-borne encephalitis virus infected cells during the lag phase of interferon activation showed that, in addition to interferon and interferon-stimulated genes (ISG), the genes involved in the unfolded protein response (UPR) were modulated. Intriguingly, this response was induced before interferon transcription. Infection in conditions of UPR priming led to early activation of IRF3, interferon and ISGs transcription, stress granules formation and inhibition of viral replication. This antiviral response in turn was dependent on the IRE1 arm of the UPR and on RIG-I, but was independent of the canonical interferon secondary signalling. Other members of the Flavivirus family such as West Nile virus, Dengue virus and Zika virus were also sensitive to UPR priming. These results demonstrate that the UPR is not only a physiological reaction of the cell to infection, but also favors the induction of the innate antiviral response. For the first time the synergy of the UPR with innate signalling is explained at the molecular level for a viral infection.
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