In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus

Publication date: Available online 11 June 2015 Source:Cell Reports Author(s): Asiel A. Benitez , Maryline Panis , Jia Xue , Andrew Varble , Jaehee V. Shim , Amy L. Frick , Carolina B. López , David Sachs , Benjamin R. tenOever Responding to an influenza A virus (IAV) infection demands an effective intrinsic cellular defense strategy to slow replication. To identify contributing host factors to this defense, we exploited the host microRNA pathway to perform an in vivo RNAi screen. To this end, IAV, lacking a functional NS1 antagonist, was engineered to encode individual siRNAs against antiviral host genes in an effort to rescue attenuation. This screening platform resulted in the enrichment of strains targeting virus-activated transcription factors, specific antiviral effectors, and intracellular pattern recognition receptors (PRRs). Interestingly, in addition to RIG-I, the PRR for IAV, a virus with the capacity to silence MDA5 also emerged as a dominant strain in wild-type, but not in MDA5-deficient mice. Transcriptional profiling of infected knockout cells confirmed RIG-I to be the primary PRR for IAV but implicated MDA5 as a significant contributor to the cellular defense against influenza A virus. Graphical abstract Teaser Benitez et al. describe an influenza-A-virus-driven siRNA screen performed in the context of an in vivo infection. This fitness-based screening platform identified virus strains encoding siRNAs targeting interferon inducing tran...

Source: Cell Reports - June 12, 2015 Category: Cytology Source Type: research