Role of Staphylococcus aureus alpha-hemolysin in disease

项目总结 金黄色葡萄球菌是引起血液循环、下呼吸道、皮肤和软组织的主要原因。 在美国的感染。展示了病原体广泛的组织范围和毒力特性， 金黄色葡萄球菌还会引起骨髓炎、感染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和危及生命 由一种表皮松解性毒素引起的脱皮。最近的估计表明，金黄色葡萄球菌对 仅在美国每年就有50万人感染，导致1万多人死亡。一年一度的 2003年金黄色葡萄球菌感染造成的经济负担高达145亿美元。到目前为止，还没有商业上 现有的预防金黄色葡萄球菌感染的疫苗，以及成功针对这一点的新型抗菌剂 生物体一直很少。在广泛传播的疾病的背景下，已经遇到了高度缺乏的 有效、持久的抗感染策略，我们必须更详细地了解 金黄色葡萄球菌致病的分子机制。金黄色葡萄球菌α-溶血素(Hla)是一种致孔细胞毒素。 在基因组中编码，并在几乎所有的金黄色葡萄球菌菌株中表达。人类白细胞抗原在慢性粒细胞白血病发病机制中的作用 肺炎、原发和复发性皮肤感染，以及通过与ADAM10相互作用而发生的脓毒症 真核细胞受体。人类白细胞抗原是正在进行的临床疫苗和被动免疫研究的首要目标。这个 该提案的主要目标是全面了解人类白细胞抗原-ADAM10复合体是如何 损伤不同的细胞阵列并调节特定宿主组织的组织修复 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的药物。这 该建议基于四个基本发现：1)通过使用特定细胞类型的ADAM10基因敲除 ，我们已经在明确定义的疾病的特定组织中分离出了人类白细胞抗原对单个细胞的影响 各州。2)hla的作用不仅是毒性造孔的产物，而且依赖于毒素的介导。 ADAM10的激活和天然ADAM10底物的病理性切割。3)我们已经证明了 感染的生理和病理表现是人类白细胞抗原(Hla)对离散细胞作用的结果。 随着时间的推移，整合到组织中的种群。4)我们已经证明了抗Hla抗体反应是 与预防儿童金黄色葡萄球菌复发有关。通过研究揭示了 人类白细胞抗原-ADAM10复合体导致宿主细胞和组织损伤的确切机制 集中分析人类对人类白细胞抗原介导的疾病的易感性，我们预计这些研究将使 改进针对人类白细胞抗原的临床试验，并提供疾病预防和治疗的方法 干预。同时，这些研究将有助于我们更广泛地了解细菌毛孔。 形成细胞毒素。

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.