Staphylococcus aureus binds factor H to moderate complement host defense

描述（由申请方提供）：金黄色葡萄球菌是美国的一种主要健康威胁，可引起皮肤脓肿、骨感染、关节感染、肺炎、心脏感染、术后感染和植入器械感染。引起国际关注的是由耐甲氧西林沙门氏菌引起的感染数量迅速增加。金黄色葡萄球菌（MRSA）。本建议的长期目标是阐明S。促进逃避体液宿主防御功能的金黄色葡萄球菌机制是开发预防或减轻疾病的新疗法的先决条件。本方案的实验重点是鉴定S.金黄色葡萄球菌细胞壁成分结合宿主补体调节蛋白因子H，并阐明因子H对金黄色葡萄球菌的免疫调节作用。金黄色表面。因子H是一种血清蛋白，其通过使补体级联反应中的关键转化酶沿着不稳定来控制补体活化。建议的工作将建立在我们以前发表的研究结果，S。金黄色葡萄球菌结合因子H以及我们的新的初步发现，至少有两个细胞壁成分的金黄色葡萄球菌。金黄色葡萄球菌结合纯化的H因子。我们将利用研究者的体液免疫专业知识和乔治L.小赖特中心的生物医学蛋白质组学在EVMS，以实现两个具体的目标：1）阐明H因子结合S的作用。金黄色葡萄球菌对补体介导的宿主防御的影响，2）鉴定S.结合因子H的金黄色葡萄球菌细胞壁蛋白。在目标1中，我们将使用标准的微生物学和补体技术来测量因子H在S.金黄色表面。在目标2中，我们将使用标准蛋白纯化技术结合串联质谱来鉴定S。增加细胞壁中结合H因子的成分。公共卫生相关性：拟议的项目将表征金黄色葡萄球菌细胞壁和宿主免疫调节蛋白因子H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金黄色葡萄球菌感染的新靶点。

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.