The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι.
The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι.
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SARS-CoV-2 的 ORF8 蛋白通过下调 MHC-α 介导免疫逃避
DOI：
10.1073/pnas.2024202118
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发表时间：
2021-06-08
影响因子：
11.1
通讯作者：
Zhang H
中科院分区：
文献类型：
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作者：
Zhang Y;Chen Y;Li Y;Huang F;Luo B;Yuan Y;Xia B;Ma X;Yang T;Yu F;Liu J;Liu B;Song Z;Chen J;Yan S;Wu L;Pan T;Zhang X;Li R;Huang W;He X;Xiao F;Zhang J;Zhang H
我们报道了SARS-CoV-2利用其ORF 8蛋白作为一种独特的机制来改变表面MHC-Ⅰ的表达以逃避免疫监视。我们的研究对于理解SARS-CoV-2的发病机制具有重要意义，并将为正在进行的COVID-19中T细胞抗病毒免疫机制和功能的深入研究提供额外的视角。由严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）引起的COVID-19已成为全球大流行病，并已在全球范围内夺去超过200万人的生命。尽管SARS-CoV和SARS-CoV-2的基因序列具有较高的同源性，但COVID-19的临床和病理特征与SARS有显著差异。SARS-CoV-2如何以及是否逃避（细胞）免疫监视需要进一步阐明。在本研究中，我们发现SARS-CoV-2感染导致主要组织相容性复合物I类（MHC-I）在体外和体内下调。SARS-CoV-2的开放阅读框8（ORF 8）编码的病毒蛋白是所有病毒蛋白中与SARS-CoV同源性最低的，它直接与MHC-Ⅰ分子相互作用并介导其下调。在表达ORF 8的细胞中，MHC-Ⅱ分子通过自噬选择性地靶向溶酶体降解。因此，SARS-CoV-2感染的细胞对细胞毒性T淋巴细胞的裂解不太敏感。由于ORF 8蛋白损害抗原呈递系统，抑制ORF 8可能是改善免疫监视的策略。
We report that SARS-CoV-2 utilizes its ORF8 protein as a unique mechanism to alter the expression of surface MHC-Ι expression to evade immune surveillance. Our study is significant for providing an understanding of the pathogenesis of SARS-CoV-2 and will provide additional perspective to the intensive ongoing investigation into the mechanism and function of T cell antiviral immunity in COVID-19. COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2–infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.