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

• 批准号: 9906166
• 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
• 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/9906166
• 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; Major Histocompatibility Complex; Mediating; Mediator of activation protein; Methicillin; Modeling; Nitric Oxide; Operative Surgical Procedures; 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; secondary lymphoid organ; staphylococcal enterotoxin; therapeutic development; vascular inflammation

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.

该建议的目的是剖析肠毒素引起葡萄球菌的潜在机制 金黄色感染性心内膜炎（IE）。 S.金黄色葡萄球菌提出了一个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 每年在美国的个人。金黄色葡萄球菌是IE在发达国家的主要原因， 在美国，每年影响约40,000人，并杀死20％至66％的患者。 S.金黄色葡萄球菌IE也是 IE的最具侵略性，组织破坏性和致命形式。金黄色葡萄球菌IE的处理具有挑战性，需要 长时间的抗生素治疗或手术以去除感染瓣膜。耐甲氧西林的金黄色葡萄球菌感染 经常进行，使治疗复杂并增加死亡率。关于金黄色葡萄球菌毒力因子知之甚少 对于IE发育至关重要，导致这种侵略性疾病的机制至关重要。这 鉴于其发病率，严重性和致死性具有，对IE的机械理解至关重要 在过去的50年中没有减少。当前的证据表明，葡萄球菌肠毒素C（SEC）， 毒性休克综合征毒素（TSST1），肠毒素基因簇（EGC）在 IE的病因由金黄色葡萄球菌引起。肠毒素缺失/互补研究证明了 SEC，TSST1和选择EGC毒素的需求，在Aureus的开发中 阀即。葡萄球菌肠毒素以其有效的超抗原特性而闻名，导致CD4+ T细胞依赖性细胞因子风暴导致炎症综合征，毒性休克综合征或败血性休克。 虽然自适应免疫系统激活是葡萄球菌肠毒素的特征，但这并不是他们的唯一 生物功能。肠毒素还直接与内皮细胞，上皮细胞和脂肪细胞相互作用 机制与超抗原活性无关。在上皮细胞中，激活取决于A 十二肽位于分子中央A螺旋的底部。在AIM 1中，我们将使用压力 表达与T细胞受体，MHC-II受体或内皮相互作用的能力灭活的肠毒素 细胞和IE的兔模型，以确定IE是由于超抗活性或十二肽 - 介导的效果，或两者兼而有之。 IE是主动脉内皮的感染。感染和炎症 血管内皮是众所周知的血管病理介质，例如动脉粥样硬化。因此， AIM 2将确定肠毒素影响内皮促进IE发育的机制。 为此，我们将使用IE的Rabbit模型，兔子主动脉膨胀文化模型和新开发的 人主动脉内皮细胞系在体内阐明机制，体内和体外。我们期望我们的 提出的研究生成数据，这些数据将大大提高我们对金黄色葡萄球菌的理解并提供 预后和治疗价值的见解，以降低IE严重性和死亡率。