title: In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus.
abstract: 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.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Asiel A
authors.initials: AA
authors.lastname: Benitez
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Maryline
authors.initials: M
authors.lastname: Panis
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Varble
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jaehee V
authors.initials: JV
authors.lastname: Shim
authors.affiliation: Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Frick
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Carolina B
authors.initials: CB
authors.lastname: López
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sachs
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: benjamin.tenoever@mssm.edu.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: tenOever
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000502:physiology*; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D034622:RNA Interference; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication
chemical_list: C437968:PLAAT4 protein, human; D018168:Receptors, Retinoic Acid; D017361:Viral Nonstructural Proteins; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1