Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.
NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
EMBO J. 2021 Sep 15;40(18):e108249. doi: 10.15252/embj.2021108249. Epub 2021 Aug 4.
SARS-CoV-2 is an emerging coronavirus that causes dysfunctions in multiple human cells and tissues. Studies have looked at the entry of SARS-CoV-2 into host cells mediated by the viral spike protein and human receptor ACE2. However, less is known about the cellular immune responses triggered by SARS-CoV-2 viral proteins. Here, we show that the nucleocapsid of SARS-CoV-2 inhibits host pyroptosis by blocking Gasdermin D (GSDMD) cleavage. SARS-CoV-2-infected monocytes show enhanced cellular interleukin-1β (IL-1β) expression, but reduced IL-1β secretion. While SARS-CoV-2 infection promotes activation of the NLRP3 inflammasome and caspase-1, GSDMD cleavage and pyroptosis are inhibited in infected human monocytes. SARS-CoV-2 nucleocapsid protein associates with GSDMD in cells and inhibits GSDMD cleavage in vitro and in vivo. The nucleocapsid binds the GSDMD linker region and hinders GSDMD processing by caspase-1. These insights into how SARS-CoV-2 antagonizes cellular inflammatory responses may open new avenues for treating COVID-19 in the future.
SARS-CoV-2 是一种新兴的冠状病毒，可导致多种人体细胞和组织功能障碍。研究已经观察到病毒刺突蛋白和人类受体 ACE2 介导的 SARS-CoV-2 进入宿主细胞。然而，对于 SARS-CoV-2 病毒蛋白引发的细胞免疫反应知之甚少。在这里，我们表明，SARS-CoV-2 的核衣壳通过阻止 Gasdermin D (GSDMD) 切割来抑制宿主细胞焦亡。SARS-CoV-2 感染的单核细胞显示出增强的细胞白细胞介素 1β (IL-1β) 表达，但 IL-1β 分泌减少。虽然 SARS-CoV-2 感染促进了 NLRP3 炎性体和半胱天冬酶-1 的激活，但在感染的人单核细胞中 GSDMD 切割和焦亡受到抑制。SARS-CoV-2 核衣壳蛋白在细胞中与 GSDMD 结合，并在体外和体内抑制 GSDMD 切割。核衣壳结合 GSDMD 连接区，并阻碍半胱天冬酶-1 对 GSDMD 的加工。这些关于 SARS-CoV-2 如何拮抗细胞炎症反应的见解可能为未来治疗 COVID-19 开辟新途径。
