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 冠状病毒病2019年(新冠肺炎)大流行与一种新发烧的出现有关 儿科实体称为儿童多系统炎症综合征(MIS-C)，涉及全身性 炎症过度，多器官受累和胃肠道症状。在某些情况下，这种综合征还 表现出的临床特征，如持续发烧、皮疹、结膜炎和全身疼痛 四肢，这反映了在川崎病(KD)期间观察到的一些特征。MIS-C患者病情危重 并伴有明显的心源性休克和显著的心肌功能障碍。虽然最初被指定为 由于有几个让人联想到KD的特征，所以被认为是川崎式的 严重急性呼吸综合征冠状病毒2(SARS-CoV-2)可在儿童中引发KD，无论 临床实验室和心脏检查结果表明，MISC和KD是不同的实体，而MISC 与由细菌或病毒超抗原触发的中毒性休克综合征(TSS)有更多的相似之处。 认识到美国国立卫生研究院的战略计划和对2019年冠状病毒病(COVID- 19)及其病原体SARS-CoV-2，在此，我们建议通过添加以下内容来扩大我们R01的计划研究 SARS-CoV-2超抗原活性及其与猪瘟发病关系的实验研究 M IS-C。我们对SARS-CoV-2病毒的初步计算分析表明，该病毒具有超抗原(SAG)。 S1S和S2S蛋白之间的基序。然而，这个具体的发现需要在生物学上进行评估。 并用人外周血单核细胞进行体外实验。 因此，我们假设KD和MIS-C是由不同的免疫机制触发的不同实体， 而在MIS-C患者中观察到的异常免疫反应是SARS-CoV-2超抗原性的结果 刺激。我们建议调查SARS-CoV-2 SAG基序触发的假设 MISC患者和重症新冠肺炎患者的高炎症状态 特异性目标1)确定超抗原(SAG)在多系统疾病发病机制中的作用 儿童炎症性综合征患者T细胞受体特性的研究 (TCR)谱系和2)确定SARS-CoV-2的Spike蛋白是否具有超抗原样 体外和体内活性。成功完成本行政副刊的目标可以揭示 预测、预防和治疗成人MISC和严重新冠肺炎疾病的新途径。

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

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

CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract-Induced Murine Model of Kawasaki Disease.

CD8+ T细胞有助于乳酸杆菌壳细胞壁提取物诱导的川崎疾病的鼠模型的冠状动脉炎的发展。

• DOI: 10.1002/art.39939
• 发表时间: 2017-02
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Noval Rivas M;Lee Y;Wakita D;Chiba N;Dagvadorj J;Shimada K;Chen S;Fishbein MC;Lehman TJ;Crother TR;Arditi M
• 通讯作者: Arditi M

Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial).

川崎疾病儿童和早期冠状动脉异常的I/IIA期试验的基本原理和研究设计（ANAKID试验）。

• DOI: 10.1016/j.cct.2016.04.002
• 发表时间: 2016-05
• 期刊: Contemporary clinical trials
• 影响因子: 2.2
• 作者: Tremoulet AH;Jain S;Kim S;Newburger J;Arditi M;Franco A;Best B;Burns JC
• 通讯作者: Burns JC

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