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 年冠状病毒病 (COVID-19) 大流行与一种新的发热性疾病的出现有关 儿科疾病称为儿童多系统炎症综合征 (MIS-C)，涉及全身系统 在某些情况下，还会出现过度炎症、多器官受累和胃肠道症状。 临床特征，例如持续发烧、皮疹、结膜炎和全身疼痛 四肢，反映了川崎病 (KD) 患者病情危重时观察到的一些特征。 并在最初指定时出现明显的心源性休克和明显的心肌功能障碍。 由于很少有让人想起 KD 的特征，因此被称为“川崎式”，有人认为 严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 可引发儿童川崎病，但许多 临床实验室和心脏检查结果表明 MIS-C 和 KD 是不同的实体，并且 MIS-C 与由细菌或病毒超抗原引发的中毒性休克综合征（TSS）有更多相似之处。 认识到 NIH 战略计划以及对 2019 年冠状病毒病 (COVID-19) 研究的迫切需要 19) 及其病原体 SARS-CoV-2，在此我们建议通过添加来扩展 R01 的计划研究 研究 SARS-CoV-2 超抗原活性的作用及其与新冠病毒出现的关系的实验 MIS-C。我们对 SARS-CoV-2 的初步计算分析表明该病毒具有超级抗原 (SAg)。 S1 和 S2 刺突蛋白之间的基序然而，这一具体发现需要在生物学上进行评估。 MIS-C 患者和使用人类 PBMC 进行的体外实验。 因此，我们追求KD和MIS-C是由不同免疫机制触发的不同实体， 在 MIS-C 患者中观察到的异常免疫反应是 SARS-CoV-2 超抗原的结果 我们建议研究 SARS-CoV-2 SAg 基序触发的假设。 通过执行以下补充措施来治疗 MIS-C 患者和严重 COVID-19 病例的过度炎症 具体目标 1) 确定超级抗原 (SAg) 在多系统发病机制中的参与 通过 MIS-C 患者 T 细胞受体的表征来了解儿童炎症综合征 (MIS-C) (TCR) 库和 2) 确定 SARS-CoV-2 的刺突蛋白是否具有超抗原样 体外和体内活动的成功完成本行政补充的目标可以揭示。 预测、预防和治疗成人 MIS-C 和严重 COVID-19 疾病的新途径。

项目成果

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 细胞有助于干酪乳杆菌细胞壁提取物诱导的川崎病小鼠模型中冠状动脉炎的发生。

• 发表时间: 2017-02
• 作者: Noval Rivas, Magali;Lee, Youngho;Wakita, Daiko;Chiba, Norika;Dagvadorj, Jargalsaikhan;Shimada, Kenichi;Chen, Shuang;Fishbein, Michael C;Lehman, Thomas J A;Crother, Timothy R;Arditi, Moshe
• 通讯作者: Arditi, Moshe

Review: Found in Translation: International Initiatives Pursuing Interleukin-1 Blockade for Treatment of Acute Kawasaki Disease.

评论：翻译发现：国际倡议追求白细胞介素 1 阻断治疗急性川崎病。

• 发表时间: 2017
• 作者: Burns, Jane C;Koné;Kuijpers, Taco;Shimizu, Chisato;Tremoulet, Adriana;Arditi, Moshe
• 通讯作者: Arditi, Moshe

Quercetin Inhibits Inflammasome Activation by Interfering with ASC Oligomerization and Prevents Interleukin-1 Mediated Mouse Vasculitis.

槲皮素通过干扰 ASC 寡聚化来抑制炎症小体激活并预防 Interleukin-1 介导的小鼠血管炎。

• 发表时间: 2017
• 影响因子: 4.6
• 作者: Domiciano, Talita P;Wakita, Daiko;Jones, Heather D;Crother, Timothy R;Verri Jr, Waldiceu A;Arditi, Moshe;Shimada, Kenichi
• 通讯作者: Shimada, Kenichi

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

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。

• 发表时间: 2020-05-21
• 作者: Cheng, Mary Hongying;Zhang, She;Porritt, Rebecca A;Arditi, Moshe;Bahar, Ivet
• 通讯作者: Bahar, Ivet

A monoclonal antibody against staphylococcal enterotoxin B superantigen inhibits SARS-CoV-2 entry in vitro.

抗葡萄球菌肠毒素 B 超抗原的单克隆抗体可在体外抑制 SARS-CoV-2 进入。

• 发表时间: 2020-11-24
• 作者: Cheng, Mary Hongying;Porritt, Rebecca A;Rivas, Magali Noval;Krieger, James M;Ozdemir, Asli Beyza;Garcia Jr, Gustavo;Arumugaswami, Vaithilingaraja;Fries, Bettina C;Arditi, Moshe;Bahar, Ivet
• 通讯作者: Bahar, Ivet