我國學者揭示貓皰疹病毒拮抗宿主天然免疫機制

導 讀

貓I型皰疹病毒（FHV-1）是貓鼻氣管炎的病原體，可持續感染和潛伏感染，導致該病的感染率、發病率和死亡率不斷上升，成為威脅寵物貓健康的重要病原。近日，中國農業科學院哈爾濱獸醫研究所自然疫源性人獸共患病團隊在Journal of Virology雜誌在線發表了題為FHV-1 US3 blocks type I IFN signal pathway by targeting IRF3 dimerizationin a kinase-independent manner的研究論文，首次發現FHV-1的US3蛋白通過抑制IRF3二聚化拮抗I型干擾素通路激活，為有效的防控貓鼻氣管炎奠定了理論基礎。

US3 inhibits the formation of the IRF3 dimerization complex.

結果速覽

研究通過熒光素酶報告系統和過表達技術，首次發現貓I型皰疹病毒（FHV-1）US3蛋白通過抑制IRF3二聚化拮抗I型干擾素通路激活，US3是拮抗干擾素通路最強的病毒蛋白，而且其拮抗活性並不依賴US3的激酶活性，揭示貓皰疹病毒逃逸宿主I型IFN通路的機制；同時發現US3也是FHV-1入侵神經系統的重要毒力因子，US3基因缺失後導致病毒不能入侵三叉神經，且該重組病毒感染後對家貓無致病性，可為進一步研究FHV-1持續感染機制及藥物干預提供研究基礎。

Fig. 1 Screen for the viral proteins responsible for blocking IFN-β response.

Fig. 2 Identification of the US3 domain required for its anti-IFN function.

Fig. 3 US3 inhibits IRF3-mediated type I IFN signalling.

Fig. 4 US3 inhibits the formation of the IRF3 dimerization complex.

ABSTRACT

As a prevalent agentin cats, feline herpesvirus 1 (FHV-1) infection contributes to felinerespiratory disease and acute and chronic conjunctivitis. FHV-1 cansuccessfully evade the host innate immune response and persist for the lifetimeof the cat. Several mechanisms of immune evasion by human herpesviruses havebeen elucidated, but the mechanism by FHV-1 remains unknown. In this study, wescreened 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 inHEK 293T cells and CRFK feline cell line, and we identified the Ser/Thr kinaseUS3 as the most powerful inhibitor. Furthermore, we found that the anti-IFNactivity of US3 depended on its N-terminus (1-75 aa) and was independent of itskinase activity. Mechanistically, the ectopic expression of US3 selectivelyinhibited IFN regulatory factor 3 (IRF3) promoter activation. Furthermore, US3bound to the IRF association domain (IAD) of IRF3 and prevented IRF3 dimerization.Finally, US3-deleted and US3-repaired recombinant FHV-1 (rFHV-dUS3 andrFHV-rUS3, respectively) were constructed. Compared with wild-type FHV-1 andrFHV-rUS3, infection with rFHV-dUS3 induced large amounts of IFN-β in vitro andin vivo. More importantly, US3 deletion significantly attenuated virulence,reduced virus shedding and blocked the invasion of trigeminal ganglia. Theseresults indicate that FHV-1 US3 efficiently inhibits IFN induction using anovel immune evasion mechanism and that FHV-1 US3 is a potential regulator ofneurovirulence.

IMPORTANCE

Despite widespreadvaccination, the prevalence of FHV-1 remains high, suggesting that it cansuccessfully evade the host innate immune response and infect cats. In thisstudy, we screened viral proteins for inhibiting IFN pathway and identified theSer/Thr kinase US3 as the most powerful inhibitor. In contrast to other membersof alphaherpesvirus, FHV-1 US3 blocked host type I IFN pathway in akinase-independent manner and via binding to the IRF3 IAD domain and preventingIRF3 dimerization. More importantly, depletion of US3 attenuated the anti-IFNactivity of FHV-1 and prevented efficient viral replication in vitro and invivo. Also, US3 deletion significantly attenuated virulence and blocked theinvasion of trigeminal ganglia. We believe that these findings will not onlyhelp us to better understand the mechanism about how FHV-1 manipulates host IFNresponse, but also highlight the potential role of US3 in the establishment oflatent infection in vivo.

文章來源：

1.Jin Tian, YongxiangLiu, Xiaoxiao Liu, Xue Sun, Jikai Zhang and Liandong Qu*.Feline herpesvirus 1(FHV-1) US3 blocks type I IFN signal pathway by targeting IRF3 dimerization ina kinase-independent manner. JVI.2018.

Doi:10.1128/JVI.00047-18.

2.中國農科院哈爾濱獸醫研究所：哈獸研自然疫源性人獸共患病團隊揭示貓皰疹病毒拮抗宿主天然免疫機制。

本期編輯：Annabella

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