Multisystem Inflammatory Syndrome in Children (MIS-C) associated with Coronavirus Disease 2019 (COVID-19) is a newly recognized condition in which children with recent SARS-CoV-2 infection present with a constellation of symptoms including hypotension, multiorgan involvement, and elevated inflammatory markers. These symptoms and the associated laboratory values strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to MHCII molecules and T cell receptors (TCRs). Here, we used structure-based computational models to demonstrate that the SARS-CoV-2 spike (S) exhibits a high-affinity motif for binding TCR, interacting closely with both the α- and β-chains variable domains complementarity-determining regions. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in any other SARS coronavirus), which is highly similar in both sequence and structure to bacterial superantigens. Further examination revealed that this interaction between the virus and human T cells is strengthened in the context of a recently reported rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from a motif shared between the SARS viruses from the 2003 and 2019 pandemics, which has intracellular adhesion molecule (ICAM)-like character. These data suggest that the SARS-CoV-2 S may act as a superantigen to drive the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.

中文翻译：

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SARS-CoV-2 特有的插入片段表现出近来突变强化的超抗原特性。


与 2019 年冠状病毒病 (COVID-19) 相关的儿童多系统炎症综合征 (MIS-C) 是一种新认识的疾病，其中近期感染 SARS-CoV-2 的儿童会出现一系列症状，包括低血压、多器官受累和血压升高炎症标志物。这些症状和相关的实验室值与中毒性休克综合征非常相似，这是一种因致病性超抗原与 MHCII 分子和 T 细胞受体 (TCR) 结合而引发的细胞毒性适应性免疫反应的升级。在这里，我们使用基于结构的计算模型来证明 SARS-CoV-2 刺突 (S) 表现出结合 TCR 的高亲和力基序，与 α 链和 β 链可变域互补决定区密切相互作用。 S 上的结合表位具有 SARS-CoV-2 独有的序列基序（任何其他 SARS 冠状病毒中都不存在），其序列和结构与细菌超抗原高度相似。进一步的检查表明，在最近报道的欧洲 SARS-CoV-2 毒株的罕见突变 (D839Y/N/E) 的背景下，病毒与人类 T 细胞之间的这种相互作用得到了加强。此外，界面区域包括来自 2003 年和 2019 年大流行的 SARS 病毒之间共享的基序的选定残基，该基序具有细胞内粘附分子 (ICAM) 样特征。这些数据表明，SARS-CoV-2 S 可能作为超级抗原，驱动成年 COVID-19 患者中 MIS-C 和细胞因子风暴的发展，对治疗方法的开发具有重要意义。