TMEM41B is a pan-flavivirus host factor

Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication. Overall design: Genome-scale CRISPR screens targeting were performed for ZIKV (PRVABC59 strain) and YFV (Asibi strain).

黄病毒（Flaviviruses）持续威胁人类健康。这类RNA病毒通过受感染蚊子与蜱虫的叮咬传播，且常引发暴发疫情。为鉴定黄病毒感染所必需的宿主因子，我们开展了全基因组功能缺失型CRISPR-Cas9筛选。基于上述筛选结果，我们重点解析了TMEM41B与VMP1在病毒复制周期中发挥的作用。针对TMEM41B的机制研究显示，本研究检测的所有黄病毒科（Flaviviridae）成员均依赖TMEM41B完成感染。我们额外检测了12个病毒科，发现冠状病毒科（Coronaviridae）的SARS-CoV-2感染同样依赖TMEM41B。值得注意的是，东亚人群中携带率近20%的单核苷酸多态性（SNPs）可削弱黄病毒感染过程。基于本研究的机制实验结果，我们提出：TMEM41B会被招募至黄病毒RNA复制复合体中，以促进膜曲率形成，从而为病毒基因组复制构建保护性微环境。整体实验设计：本研究针对寨卡病毒（ZIKV，PRVABC59毒株）与黄热病毒（YFV，Asibi毒株）开展了全基因组规模CRISPR筛选。