Coxsackievirus cloverleaf RNA containing a 5' triphosphate triggers an antiviral response via RIG-I activation.
Upon viral infections, pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate an antiviral state associated with the production of type I interferons (IFNs) and inflammatory markers. Type I IFNs play crucial roles in innate antiviral responses by inducing expression of interferon-stimulated genes and by activating components of the adaptive immune system. Although pegylated IFNs have been used to treat hepatitis B and C virus infections for decades, they exert substantial side effects that limit their use. Current efforts are directed toward the use of PRR agonists as an alternative approach to elicit host antiviral responses in a manner similar to that achieved in a natural infection. RIG-I is a cytosolic PRR that recognizes 5' triphosphate (5'ppp)-containing RNA ligands. Due to its ubiquitous expression profile, induction of the RIG-I pathway provides a promising platform for the development of novel antiviral agents and vaccine adjuvants. In this study, we investigated whether structured RNA elements in the genome of coxsackievirus B3 (CVB3), a picornavirus that is recognized by MDA5 during infection, could activate RIG-I when supplied with 5'ppp. We show here that a 5'ppp-containing cloverleaf (CL) RNA structure is a potent RIG-I inducer that elicits an extensive antiviral response that includes induction of classical interferon-stimulated genes, as well as type III IFNs and proinflammatory cytokines and chemokines. In addition, we show that prophylactic treatment with CVB3 CL provides protection against various viral infections including dengue virus, vesicular stomatitis virus and enterovirus 71, demonstrating the antiviral efficacy of this RNA ligand.
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
Qian
Q
Feng
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
Martijn A
MA
Langereis
Division of Infectious Diseases, Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, Florida, United States of America.
David
D
Olagnier
Division of Infectious Diseases, Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, Florida, United States of America.
Cindy
C
Chiang
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Roel
R
van de Winkel
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Peter
P
van Essen
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Jan
J
Zoll
Division of Infectious Diseases, Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, Florida, United States of America.
John
J
Hiscott
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
Frank J M
FJ
van Kuppeveld
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010849:Picornaviridae / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D011122:Polyphosphates / Q000494:pharmacology; D012327:RNA Virus Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D012367:RNA, Viral / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*
C551867:5'PPP-RNA; D000998:Antiviral Agents; D016207:Cytokines; D011122:Polyphosphates; D012367:RNA, Viral; D018168:Receptors, Retinoic Acid; D053487:DEAD-box RNA Helicases; C005692:triphosphoric acid