title: Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.
abstract: The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5' triphosphate (5'ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5'pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN) signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5'pppRNA, and not by IFNα-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5'pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5'pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5'pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.
authors: Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Canada.
authors: Marie-Line
authors: ML
authors: Goulet
authors: David
authors: D
authors: Olagnier
authors: Zhengyun
authors: Z
authors: Xu
authors: Suzanne
authors: S
authors: Paz
authors: S Mehdi
authors: SM
authors: Belgnaoui
authors: Erin I
authors: EI
authors: Lafferty
authors: Valérie
authors: V
authors: Janelle
authors: Meztli
authors: M
authors: Arguello
authors: Marilene
authors: M
authors: Paquet
authors: Khader
authors: K
authors: Ghneim
authors: Stephanie
authors: S
authors: Richards
authors: Andrew
authors: A
authors: Smith
authors: Peter
authors: P
authors: Wilkinson
authors: Mark
authors: M
authors: Cameron
authors: Ulrich
authors: U
authors: Kalinke
authors: Salman
authors: S
authors: Qureshi
authors: Alain
authors: A
authors: Lamarre
authors: Elias K
authors: EK
authors: Haddad
authors: Rafick Pierre
authors: RP
authors: Sekaly
authors: Suraj
authors: S
authors: Peri
authors: Siddharth
authors: S
authors: Balachandran
authors: Rongtuan
authors: R
authors: Lin
authors: John
authors: J
authors: Hiscott
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D034622:RNA Interference; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C551867:5'PPP-RNA; D000998:Antiviral Agents; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; C437968:PLAAT4 protein, human; D012367:RNA, Viral; D018168:Receptors, Retinoic Acid; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human
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