Martin-Sancho Laura, Lewinski Mary K, Pache Lars, Stoneham Charlotte A, Yin Xin, Pratt Dexter, Churas Christopher, Rosenthal Sara B, Liu Sophie, De Jesus Paul D, O'Neill Alan M, Gounder Anshu P, Nguyen Courtney, Pu Yuan, Oom Aaron L, Miorin Lisa, Rodriguez-Frandsen Ariel, Urbanowski Matthew, Shaw Megan L, Chang Max W, Benner Christopher, Frieman Matthew B, García-Sastre Adolfo, Ideker Trey, Hultquist Judd F, Guatelli John, Chanda Sumit K
bioRxiv. 2020 Sep 30:2020.09.29.319566. doi: 10.1101/2020.09.29.319566.
A deficient interferon response to SARS-CoV-2 infection has been implicated as a determinant of severe COVID-19. To identify the molecular effectors that govern interferon control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human interferon stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors that inhibited viral entry, nucleic acid binding proteins that suppressed viral RNA synthesis, and a highly enriched cluster of ER and Golgi-resident ISGs that inhibited viral translation and egress. These included the type II integral membrane protein BST2/tetherin, which was found to impede viral release, and is targeted for immune evasion by SARS-CoV-2 Orf7a protein. Overall, these data define the molecular basis of early innate immune control of viral infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.
对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的干扰素反应不足被认为是重症新型冠状病毒肺炎（COVID-19）的一个决定因素。为了确定调控干扰素对SARS-CoV-2感染控制的分子效应器，我们进行了一项大规模的功能获得性分析，评估了人类干扰素刺激基因（ISG）对病毒复制的影响。发现有限的一部分ISG可控制病毒感染，包括抑制病毒进入的内体因子、抑制病毒RNA合成的核酸结合蛋白，以及高度富集的一组驻留在内质网和高尔基体的ISG，它们抑制病毒翻译和释放。其中包括II型整合膜蛋白BST2/拴系蛋白，它被发现会阻碍病毒释放，并且是SARS-CoV-2 Orf7a蛋白免疫逃逸的靶点。总体而言，这些数据确定了病毒感染早期固有免疫控制的分子基础，这将有助于理解影响疾病严重程度的宿主决定因素，并为COVID-19提供潜在的治疗策略。
