1. In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus
- Author
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David H. Sachs, Asiel Arturo Benitez, Maryline Panis, Carolina B. López, Jia Xue, Amy L. Frick, Andrew Varble, Jaehee V. Shim, and Benjamin R. tenOever
- Subjects
Interferon-Induced Helicase, IFIH1 ,Receptors, Retinoic Acid ,viruses ,Viral Nonstructural Proteins ,Biology ,Virus Replication ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Virus ,DEAD-box RNA Helicases ,Mice ,RNA interference ,Cell Line, Tumor ,Influenza A virus ,medicine ,Animals ,Humans ,lcsh:QH301-705.5 ,Transcription factor ,Effector ,Pattern recognition receptor ,virus diseases ,MDA5 ,Virology ,3. Good health ,lcsh:Biology (General) ,Viral replication ,Host-Pathogen Interactions ,RNA Interference - Abstract
SummaryResponding 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.
- Published
- 2015
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