Journal article
Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists
Journal of virology, v 89(15), pp 8011-8025
Aug 2015
PMID: 26018150
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5'-triphosphate (5'ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5'ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5'pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5'pppRNA structures, RIG-I aptamers, or poly(I·C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5'pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses.
The development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral response in vitro and in vivo and was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5'pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists.
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Details
- Title
- Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists
- Creators
- Cindy Chiang - Vaccine & Gene Therapy Institute of FloridaVladimir Beljanski - Vaccine & Gene Therapy Institute of FloridaKevin Yin - Vaccine & Gene Therapy Institute of FloridaDavid Olagnier - Jewish General HospitalFethia Ben Yebdri - Jewish General HospitalCourtney Steel - Vaccine & Gene Therapy Institute of FloridaMarie-Line Goulet - Jewish General HospitalVictor R DeFilippis - Oregon Health & Science UniversityDaniel N Streblow - Oregon Health & Science UniversityElias K Haddad - Vaccine & Gene Therapy Institute of FloridaLydie Trautmann - Vaccine & Gene Therapy Institute of FloridaTed Ross - Vaccine & Gene Therapy Institute of FloridaRongtuan Lin - Jewish General HospitalJohn Hiscott - Vaccine & Gene Therapy Institute of Florida
- Publication Details
- Journal of virology, v 89(15), pp 8011-8025
- Publisher
- American Society for Microbiology (ASM)
- Grant note
- R56 AI108861 / NIAID NIH HHS AI108861 / NIAID NIH HHS U19 AI109680 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Infectious Diseases (and HIV Medicine); Drexel University
- Web of Science ID
- WOS:000358277800046
- Scopus ID
- 2-s2.0-84937715615
- Other Identifier
- 991020100090304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology