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 sarbeco 病毒继续威胁着人类，突出表明需要确定病毒免疫逃避的常见机制，以做好大流行准备。细胞毒性淋巴细胞对于抗病毒免疫至关重要，并表达 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，在人肺组织和 COVID-19 患者血清中观察到，SARS-CoV-2 通过脱落表面下调 MIC-A/B 来逃避 NKG2D 识别。对 SARS-CoV-2 蛋白的系统测试表明，ORF6（一种在 sarbecoviruses 中独特保守的辅助蛋白）通过脱落导致 MIC-A/B 下调。进一步的研究表明，自然杀伤（NK）细胞可以有效杀死 SARS-CoV-2 感染的细胞并限制病毒传播。然而，用单克隆抗体 7C6 抑制 MIC-A/B 脱落，进一步增强了 NK 细胞对 SARS-CoV-2 感染细胞的活性。我们的研究结果揭示了 SARS-CoV-2 用来逃避细胞毒性免疫的策略，识别了 sarbecoviruses 之间共享的罪魁祸首免疫血管素，并提出了一种潜在的新型抗病毒免疫疗法。