An RNAi screen reveals common host-virus gene signatures: implication for anti-viral drug discovery

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 anti-Dengue agents. For this purpose, we performed the first genome-wide RNAi screen, combining two high content readouts for DENV infection (FLUO) and host cell toxicity (NUCL), against an arrayed lentiviral based shRNA library covering 16,000 genes with a redundancy of at least 5 hairpins per gene. The screen identified 1,924 gene candidates in total; of which, 1,730 gene candidates abrogated Dengue infection, while 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 interactions screens. Taken together, our findings provide novel antiviral molecular targets with the potential for drug discovery and development.