Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
Cell. 2024 May 9;187(10):2393-2410.e14. doi: 10.1016/j.cell.2024.03.026. Epub 2024 Apr 22.
SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.
SARS-CoV-2 和其他沙贝科病毒继续威胁着人类，这凸显出需要对病毒免疫逃逸的常见机制进行特征分析，以为大流行的防范做好准备。细胞毒性淋巴细胞对抗病毒免疫至关重要，它们表达 NKG2D，这是一种在哺乳动物中保守的激活受体，可识别感染诱导的应激配体（例如 MIC-A/B）。我们发现，SARS-CoV-2 通过脱落来下调 MIC-A/B 的表面表达来逃避 NKG2D 的识别，这在人肺组织和 COVID-19 患者血清中都有观察到。对 SARS-CoV-2 蛋白的系统测试表明，ORF6 是一种在沙贝科病毒中独特保守的辅助蛋白，通过脱落来负责 MIC-A/B 的下调。进一步的研究表明，自然杀伤 (NK) 细胞可有效杀死 SARS-CoV-2 感染的细胞并限制病毒的传播。然而，用单克隆抗体 7C6 抑制 MIC-A/B 的脱落可进一步增强 NK 细胞对 SARS-CoV-2 感染细胞的活性。我们的发现揭示了 SARS-CoV-2 逃避细胞毒性免疫的一种策略，鉴定了沙贝科病毒之间共有的免疫逃逸因子，并提出了一种潜在的新型抗病毒免疫疗法。
