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2016 ; 12
(9
): e1005074
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Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified
by Gene-Trap Insertional Mutagenesis
#MMPMID27632082
Cheng F
; Murray JL
; Zhao J
; Sheng J
; Zhao Z
; Rubin DH
PLoS Comput Biol
2016[Sep]; 12
(9
): e1005074
PMID27632082
show ga
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.