Systems Analysis of a RIG-I Agonist Inducing Broad Spectrum Inhibition of Virus Infectivity

PLoS Pathogens

Khader Ghneim¹  Suzanne Paz²  Alain Lamarre²  Valérie Janelle²  Ulrich Kalinke³  David Olagnier³  Stephanie Richards³  Mark Cameron³  Suraj Peri³  Peter Wilkinson³  Rafick Pierre Sekaly³  Andrew Smith³  Siddharth Balachandran⁴  Rongtuan Lin⁴  Meztli Arguello⁵  Elias K. Haddad⁵  Salman Qureshi⁶  S. Mehdi Belgnaoui⁷  Marilene Paquet⁷  Zhengyun Xu⁷  Erin I. Lafferty⁷  Marie-Line Goulet⁷  John Hiscott⁷ 

[1] Comparative Medicine & Animal Resources Centre, McGill University, Montréal, Canada;Division of Experimental Medicine, McGill University, Montréal, Canada;Division of Infectious Diseases, Vaccine & Gene Therapy Institute of Florida, Port Saint Lucie, Florida, United States of America;Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America;Immunovirology Laboratory, INRS-Institut Armand-Frappier, Laval, Quebec, Canada;Institute for Experimental Infection Research, TWINCORE, Hannover, Germany;Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Canada

关键词: Influenza;    Influenza viruses;    Gene expression;    Immune response;    Antiviral immune response;    Inflammation;    Viral replication;    Interferons;   

DOI  :  10.1371/journal.ppat.1003298

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY