Vaccinia virus induces endoplasmic reticulum stress and activates unfolded protein responses through the ATF6α transcription factor

Abstract

Background Cell responses to different stress inducers are efficient mechanisms that prevent and fight the accumulation of harmful macromolecules in the cells and also reinforce the defenses of the host against pathogens. Vaccinia virus (VACV) is an enveloped, DNA virus, belonging to the Poxviridae family. Members of this family have evolved numerous strategies to manipulate host responses to stress controlling cell survival and enhancing their replicative success. In this study, we investigated the activation of the response signaling to malformed proteins (UPR) by the VACV virulent strain—Western Reserve (WR)—or the non-virulent strain—Modified Vaccinia Ankara (MVA). Methods Through RT-PCR RFLP and qPCR assays, we detected negative regulation of XBP1 mRNA processing in VACV-infected cells. On the other hand, through assays of reporter genes for the ATF6 component, we observed its translocation to the nucleus of infected cells and a robust increase in its transcriptional activity, which seems to be important for virus replication. WR strain single-cycle viral multiplication curves in ATF6α-knockout MEFs showed reduced viral yield. Results We observed that VACV WR and MVA strains modulate the UPR pathway, triggering the expression of endoplasmic reticulum chaperones through ATF6α signaling while preventing IRE1α-XBP1 activation. Conclusions The ATF6α sensor is robustly activated during infection while the IRE1α-XBP1 branch is down-regulated.

Manipulation of unfolded protein response by zoonotic vaccinia virus strains Guarani P1 and Passatempo

“…Our results are corroborated by another study of our research group in which we evaluated the activation of ER stress pathways during infection by two different laboratory VACV strains: WR virus (a replicative strain) and MVA (a non-replicative strain). 24 The nuclear translocation of ATF6 was detected after infection by MVA and WR viruses; however, because they are viral samples with different profiles, the activation of ATF6 also occurs differently in relation to the maximum levels of activation and kinetics. That may suggest that the activation of ATF6 in the early and intermediate stages may be related to genes encoded by the WR virus that are absent in the genome of the MVA virus.…”

“…Infection by both viruses is even able to neutralize the splicing of tunicamycin-induced XBP1. 24 XBP1 processing plays a role in immunity mechanisms, being important for macrophage cytokine production. 7,34 Also, VACVs interfere with the signaling of TLRs which in turn can activate XBP1.…”