Flaviviruses replicate in membranous factories associated with the endoplasmic reticulum (ER). Significant levels of flavivirus polyprotein integration contribute to ER stress and the host cell may exhibit an Unfolded Protein Response (UPR) to this protein accumulation, stimulating appropriate cellular responses such as adaptation, autophagy or cell death. These different stress responses support other antiviral strategies initiated by infected cells and can help to overcome viral infection. In epithelial A549 cells, a model currently used to study the flavivirus infection cycle and the host cell responses, all three pathways leading to UPR are activated during infection by Dengue virus (DENV), Yellow Fever virus (YFV) or West Nile virus (WNV). In the present study, we investigated the capacity of ZIKA virus (ZIKV) to induce ER stress in A549 cells. We observed that the cells respond to ZIKV infection by implementing an UPR through activation of the IRE1 and PERK pathway without activation of the ATF6 branch. By modulating the ER stress response, we found that UPR inducers significantly inhibit ZIKV replication. Interestingly, our findings provide evidence that ZIKV could manipulate the UPR to escape this host cell defence system by downregulating GRP78/BiP expression. This subversion of GRP78 expression could lead to unresolved and persistent ER stress which can be a benefit for virus growth.

黄病毒在与内质网（ER）相关的膜状工厂中复制。黄病毒多蛋白整合的显着水平导致内质网应激，宿主细胞可能对该蛋白积聚表现出未折叠的蛋白应答（UPR），从而刺激适当的细胞应答，例如适应，自噬或细胞死亡。这些不同的应激反应支持被感染细胞启动的其他抗病毒策略，并可以帮助克服病毒感染。在目前用于研究黄病毒感染周期和宿主细胞应答的模型的上皮A549细胞中，感染登革热病毒（DENV），黄热病病毒（YFV）或西尼罗河病毒（WNV）的过程中，激活UPR的所有三种途径均被激活）。在目前的研究中，我们研究了ZIKA病毒（ZIKV）诱导A549细胞内质网应激的能力。我们观察到细胞通过激活IRE1和PERK途径而不激活ATF6分支来实现UPR，从而对ZIKV感染产生反应。通过调节ER应激反应，我们发现UPR诱导剂显着抑制ZIKV复制。有趣的是，我们的发现提供了证据，表明ZIKV可以通过下调GRP78 / BiP表达来操纵UPR以逃避该宿主细胞防御系统。GRP78表达的这种颠覆可能导致无法解决的持久性ER应激，这可能有利于病毒的生长。我们发现，UPR诱导剂显着抑制ZIKV复制。有趣的是，我们的发现提供了证据，表明ZIKV可以通过下调GRP78 / BiP表达来操纵UPR以逃避该宿主细胞防御系统。GRP78表达的这种颠覆可能导致无法解决的持久性ER应激，这可能有利于病毒的生长。我们发现，UPR诱导剂显着抑制ZIKV复制。有趣的是，我们的发现提供了证据，表明ZIKV可以通过下调GRP78 / BiP表达来操纵UPR逃脱该宿主细胞防御系统。GRP78表达的这种颠覆可能导致无法解决的持续性ER应激，这可能有利于病毒生长。