Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response.
RIG-I is a cytosolic sensor critically involved in the activation of the innate immune response to RNA virus infection. In the present study, we evaluated the inhibitory effect of a RIG-I agonist on the replication of two emerging arthropod-borne viral pathogens, dengue virus (DENV) and chikungunya virus (CHIKV), for which no therapeutic options currently exist. We demonstrate that when a low, noncytotoxic dose of an optimized 5'triphosphorylated RNA (5'pppRNA) molecule was administered, RIG-I stimulation generated a robust antiviral response against these two viruses. Strikingly, 5'pppRNA treatment before or after challenge with DENV or CHIKV provided protection against infection. In primary human monocytes and monocyte-derived dendritic cells, the RIG-I agonist blocked both primary infection and antibody-dependent enhancement of DENV infection. The protective response against DENV and CHIKV induced by 5'pppRNA was dependent on an intact RIG-I/MAVS/TBK1/IRF3 axis and was largely independent of the type I IFN response. Altogether, this in vitro analysis of the antiviral efficacy of 5'pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV.


OBJECTIVE
DENV and CHIKV are two reemerging mosquito-borne viruses for which no therapeutic options currently exist. Both viruses overlap geographically in tropical regions of the world, produce similar fever-like symptoms, and are difficult to diagnose. This study investigated the inhibitory effect of a RIG-I agonist on the replication of these two viruses. RIG-I stimulation using 5'pppRNA before or after DENV or CHIKV infection generated a protective antiviral response against both pathogens in immune and nonimmune cells; interestingly, the protective response against the viruses was largely independent of the classical type I interferon response. The antiviral efficacy of 5'pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV.
Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA.
David
D
Olagnier
Florine E M
FE
Scholte
Cindy
C
Chiang
Irina C
IC
Albulescu
Carmen
C
Nichols
Zhong
Z
He
Rongtuan
R
Lin
Eric J
EJ
Snijder
Martijn J
MJ
van Hemert
John
J
Hiscott
D018354:Alphavirus Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D000818:Animals; D002460:Cell Line; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology*; D003715:Dengue / Q000235:genetics / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D051379:Mice; D011971:Receptors, Immunologic; D014779:Virus Replication
D007370:Interferon Type I; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases