A Role of Unfolded Protein Response in the Cellular Response to Flavivirus Infection

Flaviviruses are responsible for a myriad of epidemics globally. Factors like movement and climate change perpetuate their spread making control rather challenging. The understanding of host-virus interactions is therefore cornerstone in attempts to produce efficient vaccines and/or therapies. The host immune system is indispensable in fighting infections but viruses have developed evasion strategies which abrogate the response that would otherwise function in virus clearance. The unfolded protein response (UPR), an intrinsic cellular proteostasis pathway is increasingly associated with innate immunity in response to cellular insults including viral infection. UPR activation by external stimuli elicits an earlier induction of IFNβ and antiviral ISGs suggesting UPR as a priming event that potentiates a more robust response against flaviviruses. Prerequisite to the core of this study, an analysis of the effects of TM and TG (UPR chemical inducers) as used in our current experimental settings show that they are only cytostatic but not cytotoxic. Afterwards, I delve into the search for alternative UPR inducers as potential alternatives for the ones currently in use. I show that E, NS1 and NS2B proteins of TBEV can induce UPR and several antiviral ISGs when ectopically expressed, an effect that inhibits TBEV in infection. Of the three proteins studied, NS2B seems to be the most potent inducer of UPR and antiviral ISGs. Furthermore, expression of NS2B together with RIG-I augments the IFNβ promoter activity suggesting a possible role in innate signaling independent of infection. The findings of this work open up possible avenues that require further investigation particularly in the case of NS2B, which is not a well-documented flavivirus protein apart from the context of its function as a protease cofactor. The mechanism by which it induces ER stress is especially intriguing because unlike E and NS1 proteins, it is not a glycoprotei