Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation.
Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation.
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DOI：
10.1073/pnas.2010722117
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发表时间：
2020-10-13
影响因子：
11.1
通讯作者：
Bahar I
中科院分区：
文献类型：
--
作者：
Cheng MH;Zhang S;Porritt RA;Noval Rivas M;Paschold L;Willscher E;Binder M;Arditi M;Bahar I
在严重的COVID-19患者中观察到一种让人想起中毒性休克综合征（TSS）的高度炎症综合征，包括患有儿童多系统炎症综合征（MIS-C）的儿童。TSS通常由刺激适应性免疫系统过度激活的病原性超抗原引起。我们发现，SARS-CoV-2刺突蛋白含有与细菌超抗原高度相似的序列和结构基序，并可能直接结合T细胞受体。我们进一步报告了COVID-19严重炎症过度患者的T细胞受体谱系，以支持这种超抗原效应。值得注意的是，超抗原样基序在其他SARS家族冠状病毒中不存在，这可能解释了SARS-CoV-2引起MIS-C和在成人COVID-19中观察到的细胞因子风暴的独特潜力。与COVID-19相关的儿童多系统炎症综合征（MIS-C）是最近在严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的儿童中发现的一种新疾病。这些患有严重炎症的儿童和成人患者表现出一系列与中毒性休克综合征非常相似的症状，中毒性休克综合征是病原性超抗原与T细胞受体（TCR）和/或主要组织相容性复合物II类（MHCII）分子结合后引发的细胞毒性适应性免疫应答的升级。在这里，使用基于结构的计算模型，我们证明了SARS-CoV-2刺突（S）糖蛋白表现出结合TCR的高亲和力基序，并可能与MHCII形成三元复合物。S上的结合表位具有SARS-CoV-2特有的序列基序（在其他SARS相关冠状病毒中不存在），其在序列和结构上与细菌超抗原葡萄球菌肠毒素B高度相似。这种病毒和人类T细胞之间的相互作用可以通过来自SARS-CoV-2欧洲毒株的罕见突变（D839 Y/N/E）来加强。此外，界面区域包括来自2003年和2019年大流行的SARS病毒之间共享的细胞间粘附分子（ICAM）样基序的选定残基。受体结合结构域上的神经毒素样序列基序也表现出结合TCR的高趋势。对成年COVID-19患者TCR谱的分析表明，患有严重炎症性疾病的患者表现出与超抗原激活一致的TCR偏斜。这些数据表明，SARS-CoV-2 S可能作为超抗原在成年COVID-19患者中引发MIS-C以及细胞因子风暴的发展，这对治疗方法的发展具有重要意义。
A hyperinflammatory syndrome reminiscent of toxic shock syndrome (TSS) is observed in severe COVID-19 patients, including children with Multisystem Inflammatory Syndrome in Children (MIS-C). TSS is typically caused by pathogenic superantigens stimulating excessive activation of the adaptive immune system. We show that SARS-CoV-2 spike contains sequence and structure motifs highly similar to those of a bacterial superantigen and may directly bind T cell receptors. We further report a skewed T cell receptor repertoire in COVID-19 patients with severe hyperinflammation, in support of such a superantigenic effect. Notably, the superantigen-like motif is not present in other SARS family coronaviruses, which may explain the unique potential for SARS-CoV-2 to cause both MIS-C and the cytokine storm observed in adult COVID-19. Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to T cell receptors (TCRs) and/or major histocompatibility complex class II (MHCII) molecules. Here, using structure-based computational models, we demonstrate that the SARS-CoV-2 spike (S) glycoprotein exhibits a high-affinity motif for binding TCRs, and may form a ternary complex with MHCII. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin B. This interaction between the virus and human T cells could be strengthened by a rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from an intercellular adhesion molecule (ICAM)-like motif shared between the SARS viruses from the 2003 and 2019 pandemics. A neurotoxin-like sequence motif on the receptor-binding domain also exhibits a high tendency to bind TCRs. Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation. These data suggest that SARS-CoV-2 S may act as a superantigen to trigger the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.
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