美国麻省理工学院和哈佛大学Wilfredo F. Garcia-Beltran和Julie Boucau共同合作，近期取得重要工作进展。他们研究发现了β属冠状病毒B对NKG2D介导的细胞毒性免疫的逃逸。相关研究结果2024年4月22日在线发表于《细胞》杂志上。

据介绍，严重急性呼吸系统综合征冠状病毒2型（SARS-CoV-2）和其他β属冠状病毒B（sarbecovirus）继续威胁着人类，这突出表明需要描述病毒免疫逃避的常见机制，以备大流行。细胞毒性淋巴细胞对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（如MIC-A/B）。

研究人员发现，在人肺组织和新冠肺炎（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蛋白的系统测试显示，ORF6是一种在β属冠状病毒B中唯一保守的辅助蛋白，通过脱落负责MIC-A/B的下调。进一步的研究表明，自然杀伤细胞有效地杀死了受SARS-CoV-2感染的细胞，并限制了病毒的传播。

然而，单克隆抗体7C6对MIC-A/B脱落的抑制进一步增强了NK细胞对SARS-CoV-2感染细胞的活性。

总之，这一发现揭示了SARS-CoV-2逃避细胞毒性免疫的策略，确定了β属冠状病毒B之间共享的罪魁祸首免疫逃逸蛋白，并提出了一种潜在的新型抗病毒免疫疗法。

附：英文原文

Title: Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses

Author: Jordan A. Hartmann, Marcella R. Cardoso, Maria Cecilia Ramiro Talarico, Devin J. Kenney, Madison R. Leone, Dagny C. Reese, Jacquelyn Turcinovic, Aoife K. O’Connell, Hans P. Gertje, Caitlin Marino, Pedro E. Ojeda, Erich V. De Paula, Fernanda A. Orsi, Licio Augusto Velloso, Thomas R. Cafiero, John H. Connor, Alexander Ploss, Angelique Hoelzemer, Mary Carrington, Amy K. Barczak, Nicholas A. Crossland, Florian Douam, Julie Boucau, Wilfredo F. Garcia-Beltran

Issue&Volume: 2024-04-22

Abstract: SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting theneed to characterize common mechanisms of viral immune evasion for pandemic preparedness.Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activatingreceptor 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 downregulationof 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 proteinuniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulationvia shedding. Further investigation demonstrated that natural killer (NK) cells efficientlykilled SARS-CoV-2-infected cells and limited viral spread. However, inhibition ofMIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activitytoward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses,and suggest a potential novel antiviral immunotherapy.

DOI: 10.1016/j.cell.2024.03.026

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00317-9