Biological role of SARS-CoV2 Superantigenic structure in hyperinflammatory syndromes

SARS-CoV2超抗原结构在高炎症综合征中的生物学作用

• 批准号: 10205906
• 负责人: Moshe Arditi
• 金额: $ 18.49万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205906
• 关键词: 2019-nCoV; Acute; Administrative Supplement; Adult; Aneurysm; Antigens; Aortic Aneurysm; B-Lymphocytes; Biological; Biology; Blood Vessels; COVID-19; COVID-19 pandemic; Cardiac; Cardiogenic Shock; Cardiovascular Diseases; Cells; Characteristics; Child; Childhood; Clinical; Communities; Computer Analysis; Conjunctivitis; Coronary artery; Critical Illness; Development; Disease; Elements; Etiology; Exanthema; Fever; Grant; Heart Diseases; Human; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-1; Laboratories; Ligands; Limb structure; Mediating; Mucocutaneous Lymph Node Syndrome; Myocardial dysfunction; Myocarditis; Myofibroblast; Pain; Parents; Pathogenesis; Pathology; Peptide antibodies; Peripheral Blood Mononuclear Cell; Play; Prevention; Proteins; Reporting; Research; Role; Signal Transduction; Specificity; Strategic Planning; Stromelysin 1; Structure; Superantigens; Syndrome; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Toxic Shock Syndrome; United States National Institutes of Health; Vascular Diseases; Vasculitis; Viral; Virus; abdominal aorta; experimental study; gastrointestinal symptom; in vitro activity; in vivo; novel; pediatric patients; peptidomimetics; prevent

PROJECT ABSTRACT The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with the emergence of a new febrile pediatric entity called multisystem inflammatory syndrome in children (MIS-C), that involved systemic hyperinflammation, multiorgan involvement and gastrointestinal symptoms. In some cases, this syndrome also demonstrated clinical attributes, such as persistent fever, rashes, conjunctivitis and generalized pain in the extremities, that mirror some features observed during Kawasaki Disease (KD). MIS-C patients are critically ill and present with prominent cardiogenic shock and impressive myocardial dysfunction. While initially designated as “Kawasaki-like” because of the few features that were reminiscent of KD, it has been suggested that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger KD in children, however many clinical laboratory as well as cardiac findings indicate that MIS-C and KD are different entities, and that MIS-C presents more similarities with toxic shock syndrome (TSS), which is triggered by bacterial or viral superantigens. In recognition of the NIH Strategic Plan and the urgent need for research on Coronavirus Disease 2019 (COVID- 19) and its causative agent, SARS-CoV-2, here we propose to expand the planned studies of our R01 by adding experiments examining the role of SARS-CoV-2 superantigenic activity and its connection to the emergence of MIS-C. Our preliminary computational analysis of SARS-CoV-2 suggest that the virus has a superantigen (SAg) motif between the S1 and S2 spike proteins. However, this specific finding needs to be assessed biologically in MIS-C patients and by in vitro experiments using human PBMCs. Therefore, we hypothesize that KD and MIS-C are distinct entities triggered by different immune mechanisms, and that the aberrant immune response observed in MIS-C patients is the result of SARS-CoV-2 superantigenic stimulation. We propose to investigate the hypothesis that the SARS-CoV-2 SAg motif triggers hyperinflammation in MIS-C patients and severe COVID-19 cases by performing the following supplemental specific AIMS 1) Determine the involvement of a Superantigen (SAg) in the pathogenesis of Multisystem Inflammatory Syndrome in Children (MIS-C) by characterization of the MIS-C patient T Cell Receptor (TCR) repertoire and 2) Determine if the Spike protein of SARS-CoV-2 possesses superantigen-like activity in vitro and in vivo. Successful completion of the aims of this administrative supplement could reveal new avenues to predict, prevent, and treat MIS-C and severe COVID-19 disease in adults.

项目摘要 2019年冠状病毒疾病（Covid-19）大流行与新的高温的出现有关 儿童（MIS-C）中称为多系统炎症综合征的儿科实体，涉及全身 高炎症，多机器人参与和胃肠道症状。在某些情况下，此综合征也 显示出临床属性，例如持续发烧，皮疹，结膜炎和普遍的疼痛 四肢，反映了川崎病（KD）期间观察到的某些特征。 MIS-C患者重病 并出现突出的心源性休克和令人印象深刻的心肌功能障碍。而最初指定 作为“川崎般的”，因为有几个让人联想到KD的功能，因此有人建议 严重的急性呼吸综合症冠状病毒2（SARS-COV-2）可以触发儿童的KD，但是许多 临床实验室以及心脏发现，表明MIS-C和KD是不同的实体，MIS-C 与毒性休克综合征（TSS）提出了更多相似之处，该综合征是由细菌或病毒超抗原触发的。 认识NIH战略计划和迫切需要冠状病毒疾病研究的需求2019年（Covid- 19）及其因果剂SARS-COV-2，我们在这里建议通过添加R01的计划研究 实验检查了SARS-COV-2超基因活性的作用及其与出现的联系 MIS-C。我们对SARS-COV-2的初步计算分析表明该病毒具有超抗原（SAG） S1和S2尖峰蛋白之间的基序。但是，这一特定发现需要在生物学上进行评估 MIS-C患者以及使用人PBMC的体外实验。 因此，我们假设KD和MIS-C是由不同的免疫组机制触发的不同实体， 并且在MIS-C患者中观察到的异常免疫响应是SARS-COV-2超抗原的结果 刺激。我们建议研究SARS-COV-2 SAG基序触发的假设 MIS-C患者和严重COVID-19病例的过度炎症，通过进行以下补充性 具体目的1）确定超抗原（SAG）参与多系统的发病机理 通过表征MIS-C患者T细胞受体的儿童炎症综合征（MIS-C） （TCR）曲目和2）确定SARS-COV-2的尖峰蛋白是否具有超抗原样 体外和体内活性。成功完成此行政补充的目标可能会揭示 用于预测，预测和治疗成人MIS-C和严重COVID疾病的新途径。

项目成果

Interleukin-1β is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease.

• DOI: 10.1161/circulationaha.111.072769
• 发表时间: 2012-03-27
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Lee Y;Schulte DJ;Shimada K;Chen S;Crother TR;Chiba N;Fishbein MC;Lehman TJ;Arditi M
• 通讯作者: Arditi M

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm.

• DOI: 10.1161/atvbaha.115.307072
• 发表时间: 2016-05
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Wakita D;Kurashima Y;Crother TR;Noval Rivas M;Lee Y;Chen S;Fury W;Bai Y;Wagner S;Li D;Lehman T;Fishbein MC;Hoffman HM;Shah PK;Shimada K;Arditi M
• 通讯作者: Arditi M

Giant cell arteritis: dendritic cells take two T's to tango.

巨细胞动脉炎：树突状细胞需要两个T才能跳探戈。

• DOI: 10.1161/circresaha.109.194266
• 发表时间: 2009
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Yilmaz,Atilla;Arditi,Moshe
• 通讯作者: Arditi,Moshe

An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations.

• DOI: 10.1101/2020.05.21.109272
• 发表时间: 2020-05-21
• 期刊: bioRxiv : the preprint server for biology
• 作者: Cheng, Mary Hongying;Zhang, She;Bahar, Ivet
• 通讯作者: Bahar, Ivet

Targeting IRE1 endoribonuclease activity alleviates cardiovascular lesions in a murine model of Kawasaki disease vasculitis.

• DOI: 10.1172/jci.insight.157203
• 发表时间: 2022-03-22
• 期刊: JCI insight
• 影响因子: 8
• 作者: Marek-Iannucci S;Yildirim AD;Hamid SM;Ozdemir AB;Gomez AC;Kocatürk B;Porritt RA;Fishbein MC;Iwawaki T;Noval Rivas M;Erbay E;Arditi M
• 通讯作者: Arditi M