The Unfolded Protein Response is required early during TBEV infection to trigger the interferon response

Flaviviruses are a major cause of disease in humans and animals worldwide. Tick-borne encephalitis virus (TBEV) is the most relevant arthropod-borne flavivirus endemic in Europe and is the etiological agent of tick-borne encephalitis, a potentially fatal infection of the central nervous system. In our recent work we demonstrated that TBEV is able to trigger the stress response of infected cells leading to the formation of stress granules (SG) (Albornoz et al. 2014). We also found that the formation of SG in TBEV infected cells is delayed, following the same delayed kinetic of the IFN response (Miorin et al. 2012). Indeed, while TBEV replication is evident at early time points post infection, SG and IFN-β mRNA become detectable only after 16 hours. Transcriptome analysis of TBEV infected cells showed that, in addition to interferon and interferon stimulated genes, also genes of the unfolded protein response (UPR) were activated. Interestingly, the spliced form of XBP1 and phosphorylation of PERK occurred early during infection (<12h) indicating that the UPR occurs before induction of interferon. We then investigated the role of the UPR as an early cellular response to the infection and as a possible trigger of the interferon response. Interestingly, when cells were infected following treatment with Tunicamycin, a known inducer of the UPR, the IFN response was already active at 8 hours post-infection and the virus titres were significantly decreased. In this condition formation of stress granules was also anticipated with the same kinetic. These data suggest that TBEV is able to evade both the stress and interferon responses and that the UPR may play a critical and unexpected role in the delayed activation of both.