Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis.
Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis.
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DOI：
10.3389/fimmu.2022.941009
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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儿童多系统炎症综合征(MIS-C)是一种儿童发热性炎症性疾病，可在最初感染或暴露SARS-CoV-2数周后发生。MIS-C涉及全身炎症和多器官受累，包括严重的心血管、胃肠道(GI)和神经系统症状。一些临床特征，如持续发热、皮疹、结膜炎和口腔粘膜改变(红唇和草莓舌)，与川崎病(KD)的特征重叠。此外，MIS-C在临床上与由细菌超抗原(SAG)触发的中毒性休克综合征(TSS)有惊人的相似之处。MIS-C和TSS的显著相似性促使人们在SARS-CoV-2病毒中寻找SAG样结构，并在SARS-CoV-2刺突1(S1)糖蛋白中发现了与葡萄球菌肠毒素B(SEB)片段高度相似的独特的SAG样基序。计算研究表明，SAG样基序与T细胞受体(TCR)和MHC II类蛋白具有很高的亲和力。免疫测序显示T细胞受体β可变区基因11-2(TRBV11-2)的扩增与MISC的严重程度和血清细胞因子水平有关，与SAG触发的免疫反应一致。对SARS-CoV-2尖峰蛋白的计算序列分析进一步发现了保守的神经毒素样基序，这些基序可能改变神经细胞功能，并导致新冠肺炎和MISC患者的神经症状。此外，在MIS-C期间检测到自身抗体，这可能表明SARS-CoV-2后自身反应和自身免疫反应的发展。最后，观察到SARS-CoV-2RNA在肠道中持续时间延长，肠道通透性增加，循环S1水平升高。因此，我们推测，持续和长期暴露于SARS-CoV-2尖峰蛋白中的病毒SAG样和神经毒素样基序可能促进自身免疫，导致急性后新冠肺炎综合征的发展，包括MISC和长冠状病毒感染，以及由SARS-CoV-2感染引起的神经系统并发症。
Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C—such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)—overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection.