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Tian J, Liu Y, Liu X, Sun X, Zhang J, Qu L. Feline herpesvirus 1 (FHV-1) US3 blocks type I IFN signal pathway by targeting IRF3 dimerization in a kinase-independent manner. J Virol. 2018 Apr 4

发布日期:2018-04-12 15:58  浏览次数:

Feline herpesvirus 1 (FHV-1) US3 blocks type I IFN signal pathway by targeting IRF3 dimerization in a kinase-independent manner
Tian J , Liu Y , Liu X , Sun X , Zhang J , Qu L
J Virol. 2018 Apr 4. pii: JVI.00047-18. doi: 10.1128/JVI.00047-18
Abstract
As a prevalent agent in cats, feline herpesvirus 1 (FHV-1) infection contributes to feline respiratory disease and acute and chronic conjunctivitis. FHV-1 can successfully evade the host innate immune response and persist for the lifetime of the cat. Several mechanisms of immune evasion by human herpesviruses have been elucidated, but the mechanism by FHV-1 remains unknown. In this study, we screened for FHV-1 ORFs responsible for inhibiting type I interferon (IFN) pathway with an IFN-β promoter reporter and an analysis of IFN-β mRNA levels in HEK 293T cells and CRFK feline cell line, and we identified the Ser/Thr kinase US3 as the most powerful inhibitor. Furthermore, we found that the anti-IFN activity of US3 depended on its N-terminus (1-75 aa) and was independent of its kinase activity. Mechanistically, the ectopic expression of US3 selectively inhibited IFN regulatory factor 3 (IRF3) promoter activation. Furthermore, US3 bound to the IRF association domain (IAD) of IRF3 and prevented IRF3 dimerization. Finally, US3-deleted and US3-repaired recombinant FHV-1 (rFHV-dUS3 and rFHV-rUS3, respectively) were constructed. Compared with wild-type FHV-1 and rFHV-rUS3, infection with rFHV-dUS3 induced large amounts of IFN-β in vitro and in vivo More importantly, US3 deletion significantly attenuated virulence, reduced virus shedding and blocked the invasion of trigeminal ganglia. These results indicate that FHV-1 US3 efficiently inhibits IFN induction using a novel immune evasion mechanism and that FHV-1 US3 is a potential regulator of neurovirulence.IMPORTANCE Despite widespread vaccination, the prevalence of FHV-1 remains high, suggesting that it can successfully evade the host innate immune response and infect cats. In this study, we screened viral proteins for inhibiting IFN pathway and identified the Ser/Thr kinase US3 as the most powerful inhibitor. In contrast to other members of alphaherpesvirus, FHV-1 US3 blocked host type I IFN pathway in a kinase-independent manner and via binding to the IRF3 IAD domain and preventing IRF3 dimerization. More importantly, depletion of US3 attenuated the anti-IFN activity of FHV-1 and prevented efficient viral replication in vitro and in vivo Also, US3 deletion significantly attenuated virulence and blocked the invasion of trigeminal ganglia. We believe that these findings will not only help us to better understand the mechanism about how FHV-1 manipulates host IFN response, but also highlight the potential role of US3 in the establishment of latent infection in vivo.

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