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PLoS Comput Biol. 2016 Sep 15;12(9):e1005074. doi: 10.1371/journal.pcbi.1005074. eCollection 2016 Sep.

Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

Cheng F1,2, Murray JL3, Zhao J4, Sheng J5, Zhao Z2,4,6,7, Rubin DH5,8,9.

Author information

1
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, Sichuan, China.
2
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
3
Zirus, Incorporated, Buford, Georgia, United States of America.
4
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
5
Division of Infectious Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
6
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
7
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
8
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
9
Research Medicine, Veterans Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.

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.

PMID:
27632082
PMCID:
PMC5025164
DOI:
10.1371/journal.pcbi.1005074
[Indexed for MEDLINE]
Free PMC Article

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