Systems Analysis of a RIG-I Agonist Inducing Broad Spectrum Inhibition of Virus Infectivity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: John Hiscott
PROVIDER: E-GEOD-60574 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.
Goulet Marie-Line ML Olagnier David D Xu Zhengyun Z Paz Suzanne S Belgnaoui S Mehdi SM Lafferty Erin I EI Janelle Valérie V Arguello Meztli M Paquet Marilene M Ghneim Khader K Richards Stephanie S Smith Andrew A Wilkinson Peter P Cameron Mark M Kalinke Ulrich U Qureshi Salman S Lamarre Alain A Haddad Elias K EK Sekaly Rafick Pierre RP Peri Suraj S Balachandran Siddharth S Lin Rongtuan R Hiscott John J
PLoS pathogens 20130425 4
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 antivi ...[more]
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Project description: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 5M-bM-^@M-^Y triphosphate (5M-bM-^@M-^Yppp) 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, 5M-bM-^@M-^YpppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, andinduction 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 5M-bM-^@M-^YpppRNA, and not by IFNM-NM-1-2bthat 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 5M-bM-^@M-^YpppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5M-bM-^@M-^YpppRNA 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 providestranscriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5M-bM-^@M-^YpppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents. A549 cells were either non-treated, treated with RNAiMax only, transfected with 5'pppRNA, or treated with IFNa-2b and analysed at 6h or 24h.
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Project description: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 5M-bM-^@M-^Y triphosphate (5M-bM-^@M-^Yppp) 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, 5M-bM-^@M-^YpppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, andinduction 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 5M-bM-^@M-^YpppRNA, and not by IFNM-NM-1-2bthat 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 5M-bM-^@M-^YpppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5M-bM-^@M-^YpppRNA 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 providestranscriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5M-bM-^@M-^YpppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents. Kinetic analysis of A549 cells treated with 5'pppRNA and analyzed at 1h, 2h, 4h, 6h, 8h, 12h, 24h or 48h.
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