Enterotoxin-Mediated Development of Staphylococcus aureus Infective Endocarditis

肠毒素介导的金黄色葡萄球菌感染性心内膜炎的发展

基本信息

批准号：
9981940
负责人：
Wilmara Salgado Pabon
金额：
$ 59.54万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-08 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981940
关键词：
Accounting Adaptive Immune System Address Adipocytes Affect Antibiotic Therapy Antigen-Presenting Cells Atherosclerosis Biological Availability Biological Process Blood Vessels CD4 Positive T Lymphocytes Cardiovascular Diseases Cell Line Cell physiology Cells Cessation of life Characteristics Clinical Communities Complement Data Development Disease Disease Progression Endothelial Cells Endothelium Enterotoxins Epithelial Cells Etiology Gene Cluster Genes Genotype Goals Heart Hospitals Human Immune Impairment In Vitro Incidence Individual Infection Infective endocarditis Inflammation Inflammatory Innate Immune System Lead Lymphoid Major Histocompatibility Complex Mediating Mediator of activation protein Methicillin Modeling Nitric Oxide Operative Surgical Procedures Organ Oryctolagus cuniculus Pathogenesis Pathologic Pathology Patients Physiological Play Property Public Health Receptor Cell Reporting Risk Factors Role Septic Shock Severities Skin Soft Tissue Infections Staphylococcus aureus Stroke Syndrome T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Toxic Shock Syndrome Toxin United States Vascular Endothelium Virulence Factors alpha helix base crosslink cytokine release syndrome in vivo insight methicillin resistant Staphylococcus aureus mortality novel prognostic receptor recruit resistant strain response staphylococcal enterotoxin therapeutic development vascular inflammation

项目摘要

The goal of this proposal is to dissect the underlying mechanism by which enterotoxins cause Staphylococcus aureus infective endocarditis (IE). S. aureus present a significant clinical and public health problem, causing some of the most severe hospital- and community-associated illnesses and affecting approximately 500,000 individuals each year in the United States. S. aureus is the leading cause of IE in the developed world, affecting about 40,000 individuals per year in the U.S. and killing 20-66% of patients. S. aureus IE is also the most aggressive, tissue destructive, and lethal form of IE. Treatment of S. aureus IE is challenging, requiring prolonged antibiotic therapy or surgery to remove infected valves. Infections with methicillin-resistant S. aureus are frequent, complicate treatment, and increase mortality. Little is known about the S. aureus virulence factors critical for IE development and the mechanisms that lead to such an aggressive form of disease. The mechanistic understanding of IE is of utmost importance, given that its incidence, severity, and lethality have not been reduced in the last 50 years. Current evidence suggests that staphylococcal enterotoxin C (SEC), toxic shock syndrome toxin (TSST1), and the enterotoxin gene cluster (egc) play a novel and essential role in the etiology of IE caused by S. aureus. Enterotoxin deletion/complementation studies demonstrated the requirement of SEC, TSST1, and select egc toxins in development of S. aureus IE in a rabbit model of native valve IE. Staphylococcal enterotoxins are known for their potent superantigenic properties resulting in a CD4+ T cell dependent cytokine storm leading to inflammatory syndromes, toxic shock syndrome, or septic shock. While adaptive immune system activation is characteristic of staphylococcal enterotoxins, this is not their only biological function. Enterotoxins also directly interact with endothelial cells, epithelial cells, and adipocytes by a mechanism independent of superantigenic activity. In epithelial cells, activation is dependent on a dodecapeptide located at the base of the central a-helix of the molecule. In Aim 1, we will use strains expressing enterotoxins inactivated in ability to interact with the T cell receptor, MHC-II receptor, or endothelial cells and the rabbit model of IE to determine whether IE is due to superantigenic activity or dodecapeptide- mediated effects, or both. IE is an infection of the aortic endothelium. Infection and inflammation of the vascular endothelium are well-recognized mediators of vascular pathologies, such as atherosclerosis. Hence, Aim 2 will determine the mechanisms by which enterotoxins affect the endothelium to promote IE development. For this, we will use the rabbit model of IE, the rabbit aortic explant culture model, and the newly developed human aortic endothelial cell line to elucidate mechanisms in vivo, ex vivo, and in vitro. We expect our proposed studies to generate data that will significantly advance our understanding of S. aureus IE and provide insight of prognostic and therapeutic value to reduce IE severity and mortality.

该提案的目标是剖析肠毒素引起葡萄球菌的根本机制金黄色葡萄球菌感染性心内膜炎（IE）。金黄色葡萄球菌带来了重大的临床和公共卫生问题，导致一些最严重的医院和社区相关疾病，影响约 500,000 人每年在美国的个人。金黄色葡萄球菌是发达国家 IE 的主要原因，美国每年约有 40,000 人受到影响，并导致 20-66% 的患者死亡。金黄色葡萄球菌 IE 也是最具攻击性、组织破坏性和致命性的 IE 形式。金黄色葡萄球菌 IE 的治疗具有挑战性，需要长期抗生素治疗或手术切除受感染的瓣膜。耐甲氧西林金黄色葡萄球菌感染频繁发生，使治疗复杂化，并增加死亡率。关于金黄色葡萄球菌毒力因子知之甚少对于 IE 的发展以及导致这种侵袭性疾病的机制至关重要。这鉴于 IE 的发生率、严重程度和致死率，对 IE 机制的理解至关重要。过去50年没有减少。目前的证据表明葡萄球菌肠毒素 C (SEC)、中毒性休克综合征毒素（TSST1）和肠毒素基因簇（EGC）在由金黄色葡萄球菌引起的 IE 的病因学。肠毒素缺失/互补研究证明在天然兔模型中金黄色葡萄球菌 IE 的发育过程中 SEC、TSST1 和选择的 EGC 毒素的要求阀门 IE。葡萄球菌肠毒素以其强大的超抗原特性而闻名，可导致 CD4+ T 细胞依赖性细胞因子风暴导致炎症综合征、中毒性休克综合征或感染性休克。虽然适应性免疫系统激活是葡萄球菌肠毒素的特征，但这并不是其唯一的特征生物学功能。肠毒素还通过以下方式直接与内皮细胞、上皮细胞和脂肪细胞相互作用：机制独立于超抗原活性。在上皮细胞中，激活依赖于十二肽位于分子中央α螺旋的底部。在目标 1 中，我们将使用菌株表达肠毒素，其与 T 细胞受体、MHC-II 受体或内皮细胞相互作用的能力失活细胞和 IE 兔模型以确定 IE 是由于超抗原活性还是十二肽- 介导效应，或两者兼而有之。 IE 是主动脉内皮的感染。感染和炎症血管内皮是公认的血管病理学介质，例如动脉粥样硬化。因此，目标 2 将确定肠毒素影响内皮细胞以促进 IE 发展的机制。为此，我们将使用 IE 兔模型、兔主动脉外植体培养模型以及新开发的人主动脉内皮细胞系，以阐明体内、离体和体外机制。我们期望我们的拟议的研究生成的数据将显着增进我们对金黄色葡萄球菌 IE 的理解，并提供了解降低 IE 严重程度和死亡率的预后和治疗价值。