Journal of Integrative Agriculture ›› 2026, Vol. 25 ›› Issue (7): 2970-2981.DOI: 10.1016/j.jia.2024.11.019

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马立克氏病病毒（MDV）逃逸JAK-STAT天然免疫通路的分子机制

  

  • 收稿日期:2024-06-26 修回日期:2024-11-12 接受日期:2024-10-08 出版日期:2026-07-20 发布日期:2026-06-09

Marek’s disease virus inhibits the JAK–STAT signaling pathway to evade the innate immune response

Tong Zhou1, Peidong Guo1, Li Gao1, Rui Liu1, Changjun Liu1, Yanping Zhang1, Hongyu Cui1, Xiaole Qi1, Yongzhen Liu1, Suyan Wang1, Yuntong Chen1, Yulu Duan1, Xiaomei Wang1, 4, Yulong Gao1#, Kai Li1, 2, 3#   

  1. 1 Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China

    2 Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu 610213, China

    3 Chengdu National Agricultural Science and Technology Center, Chengdu 610213, China

    4 Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou 225009, China

  • Received:2024-06-26 Revised:2024-11-12 Accepted:2024-10-08 Online:2026-07-20 Published:2026-06-09
  • About author:#Correspondence Yulong Gao, E-mail: gaoyulong@caas.cn; Kai Li, Tel: +86-451-51051694, Fax: +86-451-51997166, E-mail: likai01@caas.cn
  • Supported by:

    This research was supported by grants from the National Natural Science Foundation of China (32270154, U20A2061), the Central Public-interest Scientific Institution Basal Research Fund, China (Y2022QC26), and the China Agricultural Research System (CARS-41-G15).

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摘要：

Janus激酶（JAK）-信号转导及转录激活因子（STAT）信号通路通过响应干扰素信号并诱导抗病毒蛋白表达，在天然免疫中发挥着至关重要的作用。马立克氏病病毒（MDV）属于α-疱疹病毒科成员，具有强大的致瘤性和免疫抑制效应。近年来的研究主要集中在MDV的致瘤机制上，而其免疫逃逸机制尚未被完全阐明。在本研究中，我们发现MDV通过抑制STAT1的磷酸化及其核易位，从而减少干扰素刺激基因（ISGs）的产生。利用双荧光素酶报告基因系统，我们筛选出了能够显著抑制干扰素刺激反应元件（ISRE）启动子活性的病毒蛋白。结果显示，Meq蛋白的过表达显著降低了ISRE启动子活性和ISGs的表达；相反，体外和体内实验表明，与野生型MDV相比，Meq缺失型MDV感染能够诱导产生更高水平的ISGs。此外，Meq还能抑制STAT1的磷酸化和核易位。进一步的实验表明，Meq可与JAK1及酪氨酸激酶2（TYK2）发生相互作用，进而阻断JAK1与STAT1之间的相互作用。Meq还通过半胱氨酸蛋白酶（caspase）介导的途径降解TYK2。体外和体内研究均证实，Meq缺失型MDV突变株的复制效率低于野生型MDV。综上所述，这些研究结果表明，Meq通过削弱JAK-STAT信号通路在MDV中发挥免疫抑制作用，从而促进其逃逸天然免疫监视机制。

Abstract:

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway plays a crucial role in innate immunity by inducing antiviral proteins in response to interferon signals.  Marek’s disease virus (MDV), a member of the alphaherpesvirus family, exerts potent tumorigenic and immunosuppressive effects.  Recent studies have primarily focused on the tumorigenic mechanisms of MDV, and the mechanism of immune evasion has not been fully understood.  In this study, we showed that MDV reduced the production of interferon-stimulated genes (ISGs) by inhibiting the phosphorylation and nuclear translocation of STAT1.  Using a dual-luciferase reporter system, we screened for viral proteins that significantly suppress interferon-stimulated response element (ISRE) promoter activity.  Meq overexpression markedly reduced ISRE promoter activity and ISG expression, whereas infection with Meq-deficient MDV induced higher ISG production in vitro and in vivo than infection with wild-type MDV.  Meq also inhibited the phosphorylation and nuclear translocation of STAT1.  Further experiments showed that Meq interacted with JAK1 and tyrosine kinase 2 (TYK2) and thereby inhibited JAK1–STAT1 interactions.  Meq degraded TYK2 via a caspase-mediated pathway.  The Meq-deficient MDV mutant replicated less efficiently than the wild-type MDV, both in vitro and in vivo.  Collectively, these findings demonstrate that Meq played an immunosuppressive role in MDV by attenuating the JAK–STAT signaling pathway, which facilitated escape from innate immune surveillance mechanisms.

Key words: Marek’s disease , JAK–STAT ,  innate immunity ,  immune evasion ,  interferon-stimulated gene