Orthogonal genome-wide screens of bat cells identify MTHFD1 as a target of broad antiviral therapy
Danielle E. Anderson, Jin Cui, Qian Ye, Baoying Huang, Ya Tan, Chao Jiang, Wenhong Zu, Jing Gong, Weiqiang Liu, So Young Kim, Biao Yan, Kristmundur Sigmundsson, Xiao Fang Lim, Fei Ye, Peihua Niu, Aaron T. Irving, Haoyu Zhang, Yefeng Tang, Xuming Zhou, Yu Wang, Wenjie Tan, Lin‐Fa Wang, Xu Tan
Abstract
cells for infection with two different viruses: mumps virus and influenza A virus, respectively. Independent screening results converged on the endocytosis pathway and the protein secretory pathway as required for both viral infections. Additionally, we revealed a general dependence of the C1-tetrahydrofolate synthase gene, MTHFD1, for viral replication in bat cells and human cells. The MTHFD1 inhibitor, carolacton, potently blocked replication of several RNA viruses, including SARS-CoV-2. We also discovered that bats have lower expression levels of MTHFD1 than humans. Our studies provide a resource for systematic inquiry into the genetic underpinnings of bat biology and a potential target for developing broad-spectrum antiviral therapy.