Functional gene discovery using RNA interference-based genomic screens to combat pathogen infection

Abstract

The rampant use of antibiotics in the last half-century has imposed an unforeseen biological cost, the unprecedented acceleration of bacterial evolution to produce drug-resistant strains to practically every approved antibiotic. This rise in antimicrobial drug resistance, alongside the failure of conventional research efforts to discover new antibiotics, may eventually lead to a public health crisis that can drastically curtail our ability to combat infectious disease. To address this public health need for novel countermeasure strategies, research efforts have recently focused on identification of genes in the host, rather than the pathogen, that are essential for successful pathogen infection, as potential targets for drug discovery. In the past decade, RNA interference (RNAi) has emerged as a powerful tool for analyzing gene function by silencing target genes through the specific destruction of their mRNAs. Based on RNAi methodology, high-throughput genome- wide assay platforms have been developed to identify candidate host genes that are manipulated by pathogens during infection. In this review, we will discuss recent strategies for RNAi-based genomic screens to investigate hostpathogen mechanisms in human cell models using both bacterial pathogens, including Salmonella typhimurium, Mycobacterium tuberculosis, and Listeria monocytogenes, and viruses, such as Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and influenza. These functional genomics studies have begun to elucidate novel pathogen virulence mechanisms and thus, may serve as the basis for the design of novel host-based inhibitor therapeutics that can block or alleviate the downstream effects of pathogen infection.