Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.

Autor: Marie-Line Goulet, David Olagnier, Zhengyun Xu, Suzanne Paz, S Mehdi Belgnaoui, Erin I Lafferty, Valérie Janelle, Meztli Arguello, Marilene Paquet, Khader Ghneim, Stephanie Richards, Andrew Smith, Peter Wilkinson, Mark Cameron, Ulrich Kalinke, Salman Qureshi, Alain Lamarre, Elias K Haddad, Rafick Pierre Sekaly, Suraj Peri, Siddharth Balachandran, Rongtuan Lin, John Hiscott
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: PLoS Pathogens, Vol 9, Iss 4, p e1003298 (2013)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1003298
Popis: 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.
Databáze: Directory of Open Access Journals
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