A Genome-Wide RNAi Screen Reveals Common Host–Virus Gene Signatures: Implication for Dengue Antiviral Drug Discovery

作者：David Ho-Keung Shum, Bhavneet Bhinder, Jeni P. Mahida, Constantin Radu, Paul Calder, Hakim Djaballah · 发表于：GEN Biotechnology · 年份：2023 · DOI：10.1089/genbio.2023.0001 · 被引用次数：2 · 研究领域：Mosquito-borne diseases and control、HIV Research and Treatment、Insect symbiosis and bacterial influences

Dengue is the most common mosquito-borne viral disease that in recent years has become a major international public health concern. Dengue is a tropical neglected disease with increasing global incidences, affecting millions of people worldwide, and without the availability of specific treatments to combat it. The identification of host-target genes essential for the virus life cycle, for which effective modulators may already exist, would provide an alternative path to a rapid drug development of the much needed antidengue agents. For this purpose, we performed the first genome-wide RNAi screen, combining two high-content readouts for dengue virus infection (DENV E infection intensity) and host cell toxicity (host cell stained nuclei), against an arrayed lentiviral-based short hairpin RNA library covering 16,000 genes with a redundancy of at least 5 hairpins per gene. The screen identified 1924 gene candidates in total; of which, 1730 gene candidates abrogated dengue infection, whereas 194 gene candidates were found to enhance its infectivity in HEK293 cells. A first pass clustering analysis of hits revealed a well-orchestrated gene-network dependency on host cell homeostasis and physiology triggering distinct cellular pathways for infectivity, replication, trafficking, and egress; a second analysis revealed a comprehensive gene signature of 331 genes common to hits identified in 28 published RNAi host-viral interaction screens. Taken together, our findings provide novel ant...