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

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

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

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

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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 alpha-herpes virus 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 gene (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.

Keywords:  Marek’s disease       JAK-STAT              innate immunity              immune evasion              interferon-stimulated gene  
Online: 12 November 2024  
Fund: 

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

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

Cite this article: 

Tong Zhou, Peidong Guo, Li Gao, Rui Liu, Changjun Liu, Yanping Zhang, Hongyu Cui, Xiaole Qi, Yongzhen Liu, Suyan Wang, Yuntong Chen, Yulu Duan, Xiaomei Wang, Yulong Gao, Kai Li. 2024. Marek’s disease virus inhibits the JAK-STAT signaling pathway to evade the innate immune response. Journal of Integrative Agriculture, Doi:10.1016/j.jia.2024.11.019

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