Role of Staphylococcus aureus alpha-hemolysin in disease

金黄色葡萄球菌α-溶血素在疾病中的作用

基本信息

批准号：
9247642
负责人：
Juliane Bubeck Wardenburg
金额：
$ 41.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247642
关键词：
Active Sites Acute suppurative arthritis due to bacteria Age Animal Model Anti-Infective Agents Antibody Response Antimicrobial Resistance Antitoxins Bacterial Infections Binding Biological Models Biology Blood Circulation Cells Cessation of life Child Clinical Clinical Trials Communicable Diseases Complex Coupled Cytotoxin Data Development Disease Disease Progression Disintegrins Drug resistance Economic Burden Enterotoxins Etiology Family Functional disorder Gastrointestinal Diseases Genetic Models Genetic Polymorphism Genetic Predisposition to Disease Genome Goals Grant Hemolysin Human Immunotherapy Individual Infection Infectious Skin Diseases Injury Intervention Investigation Knockout Mice Knowledge Life Link Lower respiratory tract structure Lung Maps Mediating Metalloproteases Modeling Molecular Molecular Chaperones Morbidity - disease rate Organism Osteomyelitis Passive Immunization Pathogenesis Pathologic Physiological Pneumonia Polymorphism Analysis Population Predisposition Prevention therapy Preventive Intervention Property Recurrence Role Sepsis Site Skin Tissue Soft Tissue Infections Staphylococcus aureus Surface Therapeutic Intervention Time Tissue Microarray Tissues Toxic Shock Syndrome Toxin Translations United States Vaccines Virulence Virulence Factors Widespread Disease Work alpha Toxin antimicrobial drug base body system cell injury cell type cellular targeting cohort design disorder prevention human disease in vivo imaging injured insight mutant neutralizing antibody novel novel strategies pathogen pre-clinical prevent receptor success targeted treatment tissue repair trait

项目摘要

PROJECT SUMMARY Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the United States. Demonstrating the broad tissue range and virulence properties of the pathogen, S. aureus also causes osteomyelitis, septic arthritis, and a spectrum of toxin-mediated entities including staphylococcal toxic shock syndrome, enterotoxin-induced gastrointestinal disease, and life-threatening desquamation caused by a family of epidermolytic toxins. Recent estimates suggest that S. aureus contributes to half a million infections per year in the United States alone, resulting in over 10,000 deaths. The annual economic burden of S. aureus infection reached $14.5 billion in 2003. To date, there is no commercially available vaccine to prevent S. aureus infection, and novel antimicrobial agents that successfully target this organism have been few. In the context of widespread disease that has been met with a paucity of highly effective, durable anti-infective strategies, it is imperative that we obtain a more detailed understanding of the molecular mechanisms of S. aureus pathogenesis. S. aureus alpha-hemolysin (Hla) is a pore-forming cytotoxin encoded in the genome and expressed by almost all S. aureus strains. Hla contributes to the pathogenesis of pneumonia, primary and recurrent skin infection, and sepsis through its interaction with ADAM10, the toxin's eukaryotic receptor. Hla is a premier target of ongoing clinical vaccine and passive immunization studies. The primary goal of this proposal is to develop a comprehensive knowledge of how the Hla-ADAM10 complex injures a diverse array of cells and modulates tissue repair within the context of specific host tissue microenvironments, thereby enhancing our knowledge of disease progression host susceptibility. This knowledge will enable the rational translation of novel anti-toxin therapies to impact human disease. This proposal is based on four fundamental discoveries: 1) Through the use of cell-type specific ADAM10 knockout mice, we have isolated the effects of Hla on individual cells within specific tissues in well-defined disease states. 2) The actions of Hla are not merely a product of toxic pore-formation, but depend on toxin-mediated activation of ADAM10 and pathologic cleavage of native ADAM10 substrates. 3) We have demonstrated that the physiologic and pathologic manifestations of infection are a composite of Hla action on discrete cell populations, integrated in the tissue over time. 4) We have demonstrated that an anti-Hla antibody response is associated with protection against recurrent S. aureus infection in children. Through studies that reveal the precise mechanism by which the Hla-ADAM10 complex results in host cell and tissue injury, coupled with focused analysis of human susceptibility to Hla-mediated disease, we anticipate that these studies will enable refinement of clinical trials targeting Hla, and inform the approach to disease prevention and therapeutic intervention. Simultaneously, these studies will contribute more broadly to our understanding of bacterial pore forming cytotoxins.

项目概要金黄色葡萄球菌是血液、下呼吸道、皮肤和软组织的主要原因美国的感染情况。展示病原体的广泛组织范围和毒力特性，金黄色葡萄球菌还会引起骨髓炎、化脓性关节炎和一系列毒素介导的实体，包括葡萄球菌中毒性休克综合征、肠毒素引起的胃肠道疾病，甚至危及生命由表皮松解毒素家族引起的脱屑。最近的估计表明金黄色葡萄球菌有助于仅在美国，每年就有 50 万人感染，导致 10,000 多人死亡。每年一度的 2003年，金黄色葡萄球菌感染的经济负担达到145亿美元。迄今为止，还没有商业化的治疗方法。预防金黄色葡萄球菌感染的可用疫苗，以及成功针对此感染的新型抗菌药物有机体已经很少了。在疾病广泛传播且缺乏高度重视的情况下有效、持久的抗感染策略，我们必须更详细地了解金黄色葡萄球菌发病机制的分子机制。金黄色葡萄球菌 α-溶血素 (Hla) 是一种成孔细胞毒素在基因组中编码并由几乎所有金黄色葡萄球菌菌株表达。 Hla 有助于以下疾病的发病机制通过与 ADAM10（毒素的真核受体。 Hla 是正在进行的临床疫苗和被动免疫研究的首要目标。这该提案的主要目标是全面了解 Hla-ADAM10 复合物如何损伤多种细胞并在特定宿主组织的范围内调节组织修复微环境，从而增强我们对疾病进展宿主易感性的了解。这知识将使新的抗毒素疗法能够合理地转化为影响人类疾病。这该提案基于四个基本发现：1) 通过使用细胞类型特异性 ADAM10 敲除小鼠，我们已经分离出 Hla 对特定疾病中特定组织内单个细胞的影响州。 2) Hla的作用不仅仅是有毒孔形成的产物，而且取决于毒素介导的 ADAM10 的激活和天然 ADAM10 底物的病理性裂解。 3）我们已经证明了感染的生理和病理表现是 Hla 对离散细胞作用的综合结果随着时间的推移融入组织中的群体。 4) 我们已经证明抗 Hla 抗体反应是与预防儿童复发性金黄色葡萄球菌感染有关。通过研究揭示 Hla-ADAM10 复合物导致宿主细胞和组织损伤的精确机制，再加上重点分析人类对 Hla 介导的疾病的易感性，我们预计这些研究将能够完善针对 Hla 的临床试验，并为疾病预防和治疗方法提供信息干涉。同时，这些研究将有助于我们更广泛地了解细菌孔形成细胞毒素。