West Nile virus envelope protein inhibits dsRNA-induced innate immune responses.
The immune response against viral infection relies on the early production of cytokines that induce an antiviral state and trigger the activation of immune cells. This response is initiated by the recognition of virus-associated molecular patterns such as dsRNA, a viral replication intermediate recognized by TLR3 and certain RNA helicases. Infection with West Nile virus (WNV) can lead to lethal encephalitis in susceptible individuals and constitutes an emerging health threat. In this study, we report that WNV envelope protein (WNV-E) specifically blocks the production of antiviral and proinflammatory cytokines induced by dsRNA in murine macrophages. This immunosuppressive effect was not dependent on TLR3 or its adaptor molecule Trif. Instead, our experiments show that WNV-E acts at the level of receptor-interacting protein 1. Our results also indicate that WNV-E requires a certain glycosylation pattern, specifically that of dipteran cells, to inhibit dsRNA-induced cytokine production. In conclusion, these data show that the major structural protein of WNV impairs the innate immune response and suggest that WNV exploits differential vector/host E glycosylation profiles to evade antiviral mechanisms.
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Alvaro
A
Arjona
Michel
M
Ledizet
Karen
K
Anthony
Nathalie
N
Bonafé
Yorgo
Y
Modis
Terrence
T
Town
Erol
E
Fikrig
D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000276:immunology; D007113:Immunity, Innate; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D025821:Polyubiquitin / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000032:analysis; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000494:pharmacology; D014902:West Nile virus / Q000276:immunology*
D016207:Cytokines; D012330:RNA, Double-Stranded; D011994:Recombinant Proteins; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D014759:Viral Envelope Proteins; D025821:Polyubiquitin; D011070:Poly I-C