Journal article
Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity
PLoS pathogens, v 9(4), pp e1003298-e1003298
25 Apr 2013
PMID: 23633948
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity
- Creators
- Marie-Line Goulet - Jewish General HospitalDavid Olagnier - Vaccine & Gene Therapy Institute of FloridaZhengyun Xu - Division of Experimental MedicineSuzanne Paz - Jewish General HospitalS Mehdi Belgnaoui - Jewish General HospitalErin I Lafferty - McGill UniversityValérie Janelle - Institut National de la Recherche ScientifiqueMeztli Arguello - Jewish General HospitalMarilene Paquet - McGill UniversityKhader Ghneim - Vaccine & Gene Therapy Institute of FloridaStephanie Richards - Vaccine & Gene Therapy Institute of FloridaAndrew Smith - Vaccine & Gene Therapy Institute of FloridaPeter Wilkinson - Vaccine & Gene Therapy Institute of FloridaMark Cameron - Vaccine & Gene Therapy Institute of FloridaUlrich Kalinke - Center for Experimental and Clinical Infection ResearchSalman Qureshi - McGill UniversityAlain Lamarre - Institut National de la Recherche ScientifiqueElias K Haddad - Division of Infectious DiseasesRafick Pierre Sekaly - Vaccine & Gene Therapy Institute of FloridaSuraj Peri - Fox Chase Cancer CenterSiddharth Balachandran - Fox Chase Cancer CenterRongtuan Lin - Jewish General HospitalJohn Hiscott - Vaccine & Gene Therapy Institute of Florida
- Publication Details
- PLoS pathogens, v 9(4), pp e1003298-e1003298
- Publisher
- Public Library of Science
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Infectious Diseases (and HIV Medicine); Drexel University
- Web of Science ID
- WOS:000318072700039
- Scopus ID
- 2-s2.0-84876854916
- Other Identifier
- 991020100082204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Parasitology
- Virology