Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion

文献类型： 外文期刊

第一作者： Li, Kai

作者： Li, Kai;Liu, Yongzhen;Xu, Zengkun;Zhang, Yu;Luo, Dan;Gao, Yulong;Liu, Changjun;Zhang, Yanping;Qi, Xiaole;Cui, Hongyu;Wang, Yongqiang;Gao, Li;Wang, Xiaomei;Qian, Yingjuan;Bao, Chenyi

作者机构：

期刊名称：PLOS PATHOGENS （ 影响因子：6.823； 五年影响因子：7.455 ）

ISSN： 1553-7366

年卷期： 2019 年 15 卷 9 期

页码：

收录情况： SCI

摘要： Author summary Marek's disease virus (MDV) is an avian oncogenic herpesvirus that causes a fatal disease in poultry worldwide. Chickens infected with MDV become more susceptible to secondary viral or bacterial infections. However, the mechanisms of MDV-induced immunosuppression and tumorigenesis remain largely unknown. The cGAS-STING pathway is crucial for innate immune responses against both microbial pathogens and intrinsic tumors. Here we identified the MDV oncoprotein, Meq, as an inhibitor of the cGAS-STING DNA-sensing pathway. Mechanistically, Meq interacted with STING and IRF7, and impaired the recruitment of TBK1 and IRF7 to the STING complex, thus inhibiting IRF7 activation and IFN-beta induction. Loss of Meq potently enhanced innate immune response, while impaired the replication and oncogenesis of MDV in chickens. Our findings reveal an important mechanism of immune evasion of MDV, instructing us on the virus-host interaction in MDV-induced lymphoma and potential new means to develop MDV vaccine. The cellular DNA sensor cGMP-AMP synthase (cGAS) detects cytosolic viral DNA via the stimulator of interferon genes (STING) to initiate innate antiviral response. Herpesviruses are known to target key immune signaling pathways to persist in an immune-competent host. Marek's disease virus (MDV), a highly pathogenic and oncogenic herpesvirus of chickens, can antagonize host innate immune responses to achieve persistent infection. With a functional screen, we identified five MDV proteins that blocked beta interferon (IFN-beta) induction downstream of the cGAS-STING pathway. Specifically, the MDV major oncoprotein Meq impeded the recruitment of TANK-binding kinase 1 and IFN regulatory factor 7 (IRF7) to the STING complex, thereby inhibiting IRF7 activation and IFN-beta induction. Meq overexpression markedly reduced antiviral responses stimulated by cytosolic DNA, whereas knockdown of Meq heightened MDV-triggered induction of IFN-beta and downstream antiviral genes. Moreover, Meq-deficient MDV induced more IFN-beta production than wild-type MDV. Meq-deficient MDV also triggered a more robust CD8+ T cell response than wild-type MDV. As such, the Meq-deficient MDV was highly attenuated in replication and lymphoma induction compared to wild-type MDV. Taken together, these results revealed that MDV evades the cGAS-STING DNA sensing pathway, which underpins the efficient replication and oncogenesis. These findings improve our understanding of the virus-host interaction in MDV-induced lymphoma and may contribute to the development of novel vaccines against MDV infection.

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