title: Engineered Mammalian RNAi Can Elicit Antiviral Protection that Negates the Requirement for the Interferon Response.
abstract: Although the intrinsic antiviral cell defenses of many kingdoms utilize pathogen-specific small RNAs, the antiviral response of chordates is primarily protein based and not uniquely tailored to the incoming microbe. In an effort to explain this evolutionary bifurcation, we determined whether antiviral RNAi was sufficient to replace the protein-based type I interferon (IFN-I) system of mammals. To this end, we recreated an RNAi-like response in mammals and determined its effectiveness to combat influenza A virus in vivo in the presence and absence of the canonical IFN-I system. Mammalian antiviral RNAi, elicited by either host- or virus-derived small RNAs, effectively attenuated virus and prevented disease independently of the innate immune response. These data find that chordates could have utilized RNAi as their primary antiviral cell defense and suggest that the IFN-I system emerged as a result of natural selection imposed by ancient pathogens.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Asiel Arturo
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: Laura Adrienne
authors.initials: LA
authors.lastname: Spanko
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Bouhaddou
authors.affiliation: Department of Genetics and Genomics, 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 Robert
authors.initials: BR
authors.lastname: tenOever
mesh_terms: D000818:Animals; D001483:Base Sequence; D021901:DNA, Intergenic / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D060467:Disease Resistance; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000235:genetics* / Q000276:immunology; D007372:Interferons / Q000502:physiology*; D055029:Inverted Repeat Sequences; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D034622:RNA Interference; D013045:Species Specificity
chemical_list: D021901:DNA, Intergenic; D004279:DNA, Viral; D035683:MicroRNAs; D007372:Interferons