Contribution of LukED to Staphylococcus aureus pathobiology

项目概要 金黄色葡萄球菌是造成大量医院和社区获得性感染的原因 全世界。金黄色葡萄球菌感染发病率的上升主要是由于以下因素的综合作用： 抗生素耐药性和与社区感染相关的菌株毒力增强。在缺席的情况下 为了开发出保护性疫苗，迫切需要旨在剖析金黄色葡萄球菌毒力策略的研究 希望找到新的靶点来产生新的治疗方法来对抗这种病原体。安 金黄色葡萄球菌的重要致病策略是产生靶向并杀死宿主细胞的外毒素。其中 这些与人类感染相关的金黄色葡萄球菌菌株可以产生多达五种不同的成孔双- 称为杀白细胞素的毒素成分。我们计划的长期目标是了解分子 这些杀白细胞素通过靶向细胞影响金黄色葡萄球菌感染的病理生理学的细节 免疫系统。本申请集中于这些毒素中的一种作为杀白细胞素模型，杀白细胞素 ED（卢克ED）。拟议研究的重要性源于我们最近的发现 LukED：(i) 与金黄色葡萄球菌血流感染小鼠致死有关的关键毒力因子，（ii）是 促进细菌体内复制，(iii) 通过靶向和杀死免疫系统促进金黄色葡萄球菌发病机制 体内细胞，以及（iv）以受体依赖性方式靶向多种宿主细胞。本研究的目标 计划的目的是了解 LukED 靶向其不同宿主受体的机制，以定义 LukED 损伤内皮细胞以促进与血流感染相关的致死性的详细信息， 并阐明 LukED 如何与其他杀白细胞素相互作用来调节发病机制。为此，我们 提议采用多学科方法，将毒素受体生化研究与初级研究相结合 人类细胞生物学和新型小鼠感染模型。从这些研究中收集的数据将提供很多 需要深入了解双组分杀白细胞素如何促进金黄色葡萄球菌的分子细节 病理学。

PROJECT SUMMARY Staphylococcus aureus is responsible for a large number of hospital- and community-acquired infections worldwide. The rise in the incidence of S. aureus infections is primarily due to a combination of increased antibiotic resistance and augmented virulence of strains associated with community infections. In the absence of a protective vaccine, studies aimed at dissecting virulence strategies of S. aureus are desperately needed with the hope of identifying novel targets for the generation of new treatments to combat this pathogen. An important pathogenic strategy of S. aureus is the production of exotoxins that target and kill host cells. Among these, S. aureus strains associated with human infections can produce up to five different pore-forming bi- component toxins known as leukocidins. The long-term objective of our program is to understand the molecular details by which these leukocidins influence the pathophysiology of S. aureus infection through targeting cells of the immune system. The present application focuses on one of these toxins as a model leukocidin, leukocidin ED (LukED). The importance of the proposed research originates from our recent discoveries that LukED: (i) is a critical virulence factor involved in the lethality of mice upon S. aureus bloodstream infection, (ii) is required for promoting bacterial replication in vivo, (iii) contributes to S. aureus pathogenesis by targeting and killing immune cells in vivo, and (iv) targets a wide array of host cells in a receptor-dependent manner. The goals of this research program are to understand the mechanisms by which LukED targets its different host receptors, to define the details by which LukED injures endothelial cells to promote the lethality associated with bloodstream infection, and to elucidate how LukED interacts with the other leukocidins to modulate pathogenesis. To this end, we propose to employ a multidisciplinary approach that combines toxin-receptor biochemical studies with primary human cell biology and novel murine models of infection. The data gathered from these studies will provide much needed insight into the molecular details of how the bi-component leukocidins contribute to S. aureus pathobiology.