Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion
Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion
复制标题
禽致癌疱疹病毒拮抗 cGAS-STING DNA 传感途径以介导免疫逃避。
DOI：
10.1371/journal.ppat.1007999
复制
发表时间：
2019-09-01
期刊：
影响因子：
6.7
通讯作者：
Wang, Xiaomei
中科院分区：
文献类型：
--
作者：
Li, Kai;Liu, Yongzhen;Wang, Xiaomei
马立克病病毒（Marek’s disease virus， MDV）是一种禽源性疱疹病毒，在世界范围内引起禽类的致命疾病。感染MDV的鸡更容易继发病毒或细菌感染。然而，mdv诱导的免疫抑制和肿瘤发生的机制在很大程度上仍然未知。cGAS-STING通路对于针对微生物病原体和内在肿瘤的先天免疫应答至关重要。在这里，我们发现MDV癌蛋白Meq是cGAS-STING dna传感途径的抑制剂。从机制上讲，Meq与STING和IRF7相互作用，破坏TBK1和IRF7向STING复合物的募集，从而抑制IRF7的激活和ifn - β的诱导。Meq缺失可增强鸡的先天免疫反应，同时削弱MDV在鸡体内的复制和致癌作用。我们的发现揭示了MDV免疫逃避的重要机制，为我们研究MDV诱导淋巴瘤的病毒-宿主相互作用提供了指导，并为开发MDV疫苗提供了潜在的新途径。细胞DNA传感器cGMP-AMP合成酶（cGAS）通过干扰素基因刺激因子（STING）检测胞内病毒DNA，启动先天抗病毒反应。已知疱疹病毒以关键的免疫信号通路为目标，在免疫能力强的宿主中持续存在。马立克病病毒（Marek's disease virus， MDV）是鸡的一种高致病性、高致癌性疱疹病毒，可拮抗宿主先天免疫反应，实现持续感染。通过功能筛选，我们发现了5种MDV蛋白阻断了cGAS-STING途径下游的干扰素诱导。具体来说，MDV主要癌蛋白Meq阻碍了tank结合激酶1和IFN调节因子7 （IRF7）向STING复合体的募集，从而抑制了IRF7的激活和IFN- β的诱导。Meq过表达可显著降低细胞质DNA刺激的抗病毒反应，而Meq敲低可增强mdv触发的ifn - β和下游抗病毒基因的诱导。此外，meq缺陷型MDV比野生型MDV诱导更多的ifn - β产生。meq缺陷型MDV也比野生型MDV触发更强的CD8+ T细胞反应。因此，与野生型MDV相比，meq缺陷MDV在复制和淋巴瘤诱导方面高度减弱。综上所述，这些结果表明MDV避开了cGAS-STING DNA传感途径，这是有效复制和肿瘤发生的基础。这些发现提高了我们对MDV诱导淋巴瘤病毒-宿主相互作用的理解，并可能有助于开发抗MDV感染的新型疫苗。
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.