Contribution of LukED to Staphylococcus aureus pathobiology

项目摘要 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 国际吧S.金黄色葡萄球菌感染主要是由于 抗生素耐药性和与社区感染相关的菌株毒力增强。在没有 的保护性疫苗，研究旨在解剖的毒力策略的S。金黄色葡萄球菌迫切需要 希望能找到新的靶点，以产生新的治疗方法来对抗这种病原体。一个 重要致病策略。金黄色葡萄球菌产生针对并杀死宿主细胞的外毒素。之间 这些，S。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 一种叫做杀白细胞素的毒素。我们项目的长期目标是了解 这些杀白细胞素影响S.金黄色葡萄球菌感染通过靶向细胞 免疫系统.本申请集中于作为杀白细胞素模型的这些毒素之一，杀白细胞素 艾德（卢克艾德）。建议的研究的重要性源于我们最近的发现，LukED：（i）是 一个关键的毒力因子参与小鼠对S.金黄色葡萄球菌血流感染，（ii）需要 促进细菌在体内的复制，（iii）有助于S.金黄色葡萄球菌的免疫靶向杀伤致病机制 细胞，和（iv）以受体依赖性方式靶向广泛的宿主细胞。这项研究的目的是 该计划的目的是了解LukED靶向其不同宿主受体的机制， LukED损伤内皮细胞以促进与血流感染相关的致死率的细节， 并阐明LukED如何与其他杀白细胞素相互作用以调节发病机制。为此我们 建议采用多学科方法，将毒素受体生化研究与初级 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S.金黄色 病理生物学

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.