title: Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.
abstract: Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase). Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B) identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline) that may be potential for antiviral indication (e.g. anti-Ebola). In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, Sichuan, China.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Feixiong
authors.identifier: 0000-0002-1251-3116
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Zirus, Incorporated, Buford, Georgia, United States of America.
authors.forename: James L
authors.initials: JL
authors.lastname: Murray
authors.affiliation: Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Junfei
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Division of Infectious Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.|Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Zhongming
authors.identifier: 0000-0002-3477-0914
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Division of Infectious Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Research Medicine, Veterans Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
authors.forename: Donald H
authors.initials: DH
authors.lastname: Rubin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D016503:Drug Delivery Systems; D055808:Drug Discovery / Q000379:methods*; D056945:Hep G2 Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D016254:Mutagenesis, Insertional / Q000379:methods*; D060066:Protein Interaction Maps / Q000187:drug effects*; D049490:Systems Biology / Q000379:methods*; D014779:Virus Replication / Q000235:genetics
chemical_list: D000998:Antiviral Agents