2.50
Hdl Handle:
http://hdl.handle.net/10033/305879
Title:
Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.
Authors:
Goulet, Marie-Line; Olagnier, David; Xu, Zhengyun; Paz, Suzanne; Belgnaoui, S Mehdi; Lafferty, Erin I; Janelle, Valérie; Arguello, Meztli; Paquet, Marilene; Ghneim, Khader; Richards, Stephanie; Smith, Andrew; Wilkinson, Peter; Cameron, Mark; Kalinke, Ulrich ( 0000-0003-0503-9564 ) ; Qureshi, Salman; Lamarre, Alain; Haddad, Elias K; Sekaly, Rafick Pierre; Peri, Suraj; Balachandran, Siddharth; Lin, Rongtuan; Hiscott, John
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.
Affiliation:
Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Canada.
Citation:
Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity. 2013, 9 (4):e1003298 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Apr-2013
URI:
http://hdl.handle.net/10033/305879
DOI:
10.1371/journal.ppat.1003298
PubMed ID:
23633948
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the department of experimental infection research ([TC] EXPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorGoulet, Marie-Lineen
dc.contributor.authorOlagnier, Daviden
dc.contributor.authorXu, Zhengyunen
dc.contributor.authorPaz, Suzanneen
dc.contributor.authorBelgnaoui, S Mehdien
dc.contributor.authorLafferty, Erin Ien
dc.contributor.authorJanelle, Valérieen
dc.contributor.authorArguello, Meztlien
dc.contributor.authorPaquet, Marileneen
dc.contributor.authorGhneim, Khaderen
dc.contributor.authorRichards, Stephanieen
dc.contributor.authorSmith, Andrewen
dc.contributor.authorWilkinson, Peteren
dc.contributor.authorCameron, Marken
dc.contributor.authorKalinke, Ulrichen
dc.contributor.authorQureshi, Salmanen
dc.contributor.authorLamarre, Alainen
dc.contributor.authorHaddad, Elias Ken
dc.contributor.authorSekaly, Rafick Pierreen
dc.contributor.authorPeri, Surajen
dc.contributor.authorBalachandran, Siddharthen
dc.contributor.authorLin, Rongtuanen
dc.contributor.authorHiscott, Johnen
dc.date.accessioned2013-11-28T11:52:06Zen
dc.date.available2013-11-28T11:52:06Zen
dc.date.issued2013-04en
dc.identifier.citationSystems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity. 2013, 9 (4):e1003298 PLoS Pathog.en
dc.identifier.issn1553-7374en
dc.identifier.pmid23633948en
dc.identifier.doi10.1371/journal.ppat.1003298en
dc.identifier.urihttp://hdl.handle.net/10033/305879en
dc.description.abstractThe 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.en
dc.language.isoenen
dc.rightsArchived with thanks to PLoS pathogensen
dc.titleSystems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.en
dc.typeArticleen
dc.contributor.departmentLady Davis Institute, Jewish General Hospital, McGill University, Montréal, Canada.en
dc.identifier.journalPLoS pathogensen

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