Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection.
Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection.
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cGAS 感知细胞质染色质激活 SARS-CoV-2 感染中的先天免疫反应
DOI：
10.1038/s41392-021-00800-3
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发表时间：
2021-11-03
影响因子：
39.3
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Zhou Z;Zhang X;Lei X;Xiao X;Jiao T;Ma R;Dong X;Jiang Q;Wang W;Shi Y;Zheng T;Rao J;Xiang Z;Ren L;Deng T;Jiang Z;Dou Z;Wei W;Wang J
2019年全球冠状病毒病(新冠肺炎)大流行是由严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)引起的，这种病毒是一种阳性核糖核酸病毒。宿主免疫系统如何感知和应对SARS-CoV-2感染在很大程度上仍未解决。在这里，我们报道了SARS-CoV-2感染通过胞浆DNA感知cGAS-STING途径激活先天免疫反应。SARS-CoV-2感染诱导细胞水平的2‘，3’-cGAMP与刺痛激活相关。CGAS识别SARS-CoV-2感染后细胞间融合而从细胞核穿梭的染色质DNA。我们进一步证明，SARS-CoV-2和宿主细胞的ACE2刺突蛋白的表达足以在细胞融合时触发细胞质染色质。此外，细胞融合时干扰素和促炎基因的表达是通过细胞质染色质-cGAS-STING途径，而不是MAVS介导的病毒RNA传感途径来实现的。最后，我们发现宿主对SARS-CoV-2的抗病毒反应需要cGAS，并且一种刺激性化合物有效地抑制病毒复制。总之，我们的研究报告了一种以前未被认识的机制，即宿主固有免疫系统对SARS-CoV-2感染的反应，是由感染细胞的细胞质染色质介导的。靶向胞浆染色质-cGAS-STING通路可能为新冠肺炎的治疗提供新的治疗机会。此外，这些发现扩展了我们在宿主防御病毒感染方面的知识，表明宿主细胞的自身核酸可以被用作警告免疫系统的“危险信号”。
The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.
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