Antagonism of the Integrated Stress Response By Tick-Borne Encephalitis Virus

Nascimento Alves, Lais (2022). Antagonism of the Integrated Stress Response By Tick-Borne Encephalitis Virus. PhD thesis The Open University.



Flaviviruses are a large family of viruses of increasing importance for human health. The host response to infection is critical to determine the outcome of the disease, particularly at early stages. In addition, they are known to rearrange the endoplasmic reticulum (ER) membrane to form characteristic replication vesicles. Membrane rearrangements and accumulation of viral proteins in the ER during replication lead to the activation of diverse cellular stress responses.

The integrated stress response (ISR) is a cellular program to restore homeostasis after exposure to different stresses, including viral infection. It can reversibly stall protein translation through phosphorylation of the translation initiation factor 2α (eIF2α). The direct effect is the formation of cytoplasmic structures called stress granules (SG), clusters of stalled mRNA, initiation factors, and RNA-binding proteins. SG have also been proposed to signal innate immune responses and are directly targeted by several viral proteins. The kinetic of the unfolded protein response (UPR) and ISR activation following Tick-Borne Encephalitis Virus (TBEV) infection have been described by our group (Carletti and Zakaria et al., 2019). Both occur early upon infection, before activation of interferon β (IFNβ) and interferon-stimulated genes (ISG). However, few SG are observed at late stages. Stimulation of infected cells with an activator of the UPR induces an earlier and stronger innate response and formation of SG.

Further, analysis of the kinases that induce eIF2α phosphorylation by the generation of knocked-down cells showed that late formation of the TBEV-induced functional SG is PERK independent but PKR dependent. These observations indicate that the UPR response per se cannot induce SG during TBEV infection. Interestingly, PKR activation is concomitant with IFNβ induction and requires unmasking and detection of viral RNA intermediates. Furthermore, it was also found that the NS4B and NS5 proteins of TBEV can inhibit PKR activation after Poly(I:C) transfection and thus prevent SG formation. Finally, cells deficient in SG formation showed a modest increase in viral replication and a lower level of IFNβ mRNA.

To conclude, I have defined the most relevant kinase involved in SG formation following TBEV infection and identified NS4B and NS5 as viral factors involved in the modulation of this pathway.

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