Zika virus inhibits eIF2α-dependent stress granule assembly

Zika virus (ZIKV), a member of the Flaviviridae family, is the most recent emerging arbovirus with pandemic potential. During infection, viruses trigger the host cell stress response, leading to changes in RNA translation and the assembly of large aggregates of stalled translation preinitiation complexes, termed stress granules (SGs). Several reports demonstrate that flaviviruses modulate the assembly of stress granules (SG). As an emerging pathogen, little is known however about how ZIKV modulates the host cell stress response. In this work, we investigate how ZIKV modulates SG assembly. We demonstrate that ZIKV negatively impacts SG assembly under oxidative stress conditions induced by sodium arsenite (Ars), a treatment that leads to the phosphorylation of eIF2α. By contrast, no measurable difference in SG assembly was observed between mock and ZIKV-infected cells treated with sodium selenite (Se) or Pateamine A (PatA), compounds that trigger eIF2α-independent SG assembly. Interestingly, ZIKV infection markedly impaired the phosphorylation of eIF2α triggered in Ars-treated infected cells, and the abrogation of SG assembly in ZIKV-infected cells is, at least in part, dependent on eIF2α dephosphorylation. These data demonstrate that ZIKV elicits mechanisms to counteract host anti-viral stress responses to promote a cellular environment propitious for viral replication.

寨卡病毒（Zika virus, ZIKV）属于黄病毒科（Flaviviridae），是新近被发现的具备大流行潜力的虫媒病毒（arbovirus）。病毒感染宿主细胞后，会触发宿主细胞应激反应，引发RNA翻译过程改变，并组装形成大量停滞的翻译预起始复合物聚集体，即应激颗粒（stress granules, SGs）。多项研究已证实，黄病毒属病毒可调控应激颗粒的组装过程。作为一种新兴病原体，目前学界对寨卡病毒如何调控宿主细胞应激反应的认知仍较为匮乏。本研究聚焦于寨卡病毒对宿主应激颗粒组装的调控机制。研究结果显示，在亚砷酸钠（sodium arsenite, Ars）诱导的氧化应激条件下——该处理会引发eIF2α的磷酸化——寨卡病毒会对宿主应激颗粒的组装产生负向调控作用。与之形成对比的是，在用硒酸钠（sodium selenite, Se）或Pateamine A（PatA）处理的细胞中，模拟感染组与寨卡病毒感染组的应激颗粒组装未出现可检测到的显著差异；这两种化合物可触发不依赖eIF2α的应激颗粒组装。值得注意的是，寨卡病毒感染显著抑制了亚砷酸钠处理的感染细胞中eIF2α的磷酸化，而寨卡病毒感染细胞内应激颗粒组装的阻断现象，至少在部分程度上依赖于eIF2α的去磷酸化过程。上述实验数据表明，寨卡病毒可通过激活相关机制对抗宿主的抗病毒应激反应，进而营造出有利于病毒复制的细胞微环境。