Department of Biological and Environmental Sciences, Le Moyne College, Syracuse, NY 13214 USA.
J.A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Viruses. 2019 Jun 18;11(6):563. doi: 10.3390/v11060563.
Following reovirus infection, cells activate stress responses that repress canonical translation as a mechanism to limit progeny virion production. Work by others suggests that these stress responses, which are part of the integrated stress response (ISR), may benefit rather than repress reovirus replication. Here, we report that compared to untreated cells, treating cells with sodium arsenite (SA) to activate the ISR prior to infection enhanced viral protein expression, percent infectivity, and viral titer. SA-mediated enhancement was not strain-specific, but was cell-type specific. While SA pre-treatment of cells offered the greatest enhancement, treatment within the first 4 h of infection increased the percent of cells infected. SA activates the heme-regulated eIF2α (HRI) kinase, which phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α) to induce stress granule (SG) formation. Heat shock (HS), another activator of HRI, also induced eIF2α phosphorylation and SGs in cells. However, HS had no effect on percent infectivity or viral yield but did enhance viral protein expression. These data suggest that SA pre-treatment perturbs the cell in a way that is beneficial for reovirus and that this enhancement is independent of SG induction. Understanding how to manipulate the cellular stress responses during infection to enhance replication could help to maximize the oncolytic potential of reovirus.
在呼肠孤病毒感染后，细胞会激活应激反应，抑制规范翻译，作为限制病毒粒子产生的一种机制。其他人的工作表明，这些应激反应是整合应激反应 (ISR) 的一部分，可能对呼肠孤病毒的复制有益，而不是抑制。在这里，我们报告说，与未处理的细胞相比，在用亚砷酸钠 (SA) 处理细胞以激活 ISR 后再感染，可以增强病毒蛋白的表达、感染率和病毒滴度。SA 介导的增强作用不是株特异性的，而是细胞类型特异性的。虽然 SA 预处理细胞提供了最大的增强效果，但在感染的前 4 小时内进行处理可以增加感染细胞的比例。SA 激活了血红素调节的 eIF2α (HRI) 激酶，该激酶磷酸化真核翻译起始因子 2α (eIF2α) 以诱导应激颗粒 (SG) 的形成。热休克 (HS)，也是 HRI 的另一种激活剂，也诱导了细胞中 eIF2α 的磷酸化和 SGs 的形成。然而，HS 对感染率或病毒产量没有影响，但确实增强了病毒蛋白的表达。这些数据表明，SA 预处理以一种对呼肠孤病毒有益的方式扰乱了细胞，并且这种增强作用与 SG 诱导无关。了解如何在感染过程中操纵细胞应激反应以增强复制，可以帮助最大限度地发挥呼肠孤病毒的溶瘤潜力。
