Staphylococcus aureus binds factor H to moderate complement host defense

金黄色葡萄球菌结合 H 因子以调节补体宿主防御

• 批准号: 7642971
• 负责人: KENJI Mason CUNNION
• 金额: $ 21.53万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642971
• 关键词: Antibiotic Resistance; Attenuated; Bacteria; Binding; Biological Assay; Biological Models; Cell Wall; Cessation of life; Chemotactic Factors; Complement; Complement 3 Convertase; Complement 3b; Complement 5a; Complement Activation; Complement Factor H; Coupled; Deposition; Development; Disease; Feedback; Fibrinogen; Fractionation; Generations; Goals; Health; Heart; Host Defense; Human; Immune; Immunology; Infection; Inflammation Mediators; International; Investigation; Joints; Mass Spectrum Analysis; Measures; Mediating; Methodology; Osteomyelitis; Pathogenesis; Pathway interactions; Pneumonia; Postoperative Period; Preparation; Prevention; Principal Investigator; Protein Binding; Proteins; Proteomics; Publishing; Research; Research Personnel; Role; Serum; Serum Proteins; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Surface; Techniques; Testing; Therapeutic; United States; Virulence; Western Blotting; Work; alternative pathway complement C3 convertase; disability; factor A; genetic regulatory protein; implantable device; methicillin resistant Staphylococcus aureus; novel; pathogen; prevent; programs; protein purification; public health relevance; skin abscess; tandem mass spectrometry

DESCRIPTION (provided by applicant): Staphylococcus aureus is a major health threat in the United States causing skin abscesses, bone infections, joint infections, pneumonias, heart infections, post-operative infections, and infections of implanted devices. Of international concern is the rapidly increasing number of infections caused by methicillin-resistant S. aureus (MRSA). The long-term objective of this proposal is to elucidate S. aureus mechanisms that facilitate evasion of humoral host defense functions as a prerequisite to the development of novel therapies to prevent or attenuate disease. The experimental focus of this proposal is to identify S. aureus cell wall components that bind the host complement regulatory protein factor H and to elucidate the immunomodulatory actions of factor H on the S. aureus surface. Factor H is a serum protein that controls complement activation by destabilizing critical convertases along the complement cascade. The proposed work will build upon our previously published findings that S. aureus binds factor H as well as our new preliminary findings that at least two cell wall components of S. aureus bind purified factor H on overlay Western blot assay. We shall take advantage of the investigator's humoral immune expertise and the proteomic expertise of the George L. Wright Jr. Center for Biomedical Proteomics at EVMS to achieve two specific aims: 1) elucidate the role of factor H binding to S. aureus on complement-mediated host defenses, 2) identify S. aureus cell wall protein(s) that bind factor H. In aim 1 we will use standard microbiologic and complement techniques to measure the effect of factor H in the destabilization of the alternative pathway C3-convertase and the terminal complement cascade C5-convertases on the S. aureus surface. In aim 2 we will use standard protein purification techniques coupled with tandem mass spectrometry to identify S. aurues cell wall components that bind factor H. PUBLIC HEALTH RELEVANCE: The proposed project will characterize interactions between Staphylococcus aureus cell wall and the host immuno-regulatory protein factor H. Understanding how this bacteria manipulates factor H will help identify new targets for prevention and treatment of Staphylococcus aureus infections.

描述（由申请人提供）：金黄色葡萄球菌是美国的主要健康威胁，可导致皮肤脓肿、骨感染、关节感染、肺炎、心脏感染、术后感染和植入设备感染。国际社会关注的是耐甲氧西林金黄色葡萄球菌 (MRSA) 引起的感染数量迅速增加。该提案的长期目标是阐明金黄色葡萄球菌促进逃避体液宿主防御功能的机制，这是开发预防或减轻疾病的新疗法的先决条件。本提案的实验重点是鉴定与宿主补体调节蛋白 H 因子结合的金黄色葡萄球菌细胞壁成分，并阐明 H 因子对金黄色葡萄球菌表面的免疫调节作用。 H 因子是一种血清蛋白，通过破坏补体级联中关键转化酶的稳定性来控制补体激活。拟议的工作将建立在我们之前发表的金黄色葡萄球菌结合 H 因子的发现以及我们新的初步发现（在重叠蛋白质印迹测定中金黄色葡萄球菌的至少两种细胞壁成分结合纯化的 H 因子）的基础上。我们将利用研究者的体液免疫专业知识和 EVMS 的 George L. Wright Jr. 生物医学蛋白质组学中心的蛋白质组学专业知识来实现​​两个具体目标：1) 阐明 H 因子与金黄色葡萄球菌结合对补体介导的宿主防御的作用，2) 鉴定结合 H 因子的金黄色葡萄球菌细胞壁蛋白。在目标 1 中，我们将使用标准微生物学和补体 测量因子 H 在金黄色葡萄球菌表面旁路途径 C3 转化酶和末端补体级联 C5 转化酶不稳定中的影响的技术。在目标 2 中，我们将使用标准蛋白质纯化技术结合串联质谱来鉴定结合 H 因子的金黄色葡萄球菌细胞壁成分。 公共健康相关性：拟议项目将描述金黄色葡萄球菌细胞壁和宿主免疫调节蛋白 H 因子之间的相互作用。了解这种细菌如何操纵 H 因子将有助于确定预防和治疗葡萄球菌的新靶点 金黄色葡萄球菌感染。