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 国际吧S.金黄色葡萄球菌感染主要是由于增加的抗生素 与社区感染有关的菌株的耐药性和毒力增加。在没有 保护性疫苗的研究，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。金黄色葡萄球菌是靶向和杀死宿主细胞的外毒素的产生。之间 这些毒素，S。与人类感染相关的金黄色葡萄球菌菌株可以产生多达四种不同的成孔性 双组分白细胞毒素。我们实验室的长期目标是了解分子细节， 其中双组分白细胞毒素影响S.金黄色葡萄球菌感染通过靶向细胞 免疫系统.本申请集中于这些毒素之一，杀白细胞素艾德（Luk艾德）。的 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.通过靶向和杀灭金黄色葡萄球菌致病 体内免疫细胞，和（iv）以受体特异性方式靶向多种白细胞。的目标 这项研究计划旨在了解LukED靶向不同白细胞的机制， 阐明LukED介导的细胞损伤对S.金黄色葡萄球菌的发病机制，并探讨 靶向LukED作为抑制S.金黄色葡萄球菌毒力为此我们 我建议采用生物化学、细胞生物学和免疫学相结合的多学科方法 利用离体组织培养感染模型和体内动物感染模型的技术。获得的结果 从这些研究将提供深入了解的分子细节，S。金黄色双组分成孔 毒素选择性地靶向并杀死宿主细胞，以及这些毒素对S.金黄色葡萄球菌发病机制

PROJECT SUMMARY: Staphylococcus aureus is responsible for a large number of hospital- and community-acquired infections worldwide. The rise in incidence of S. aureus infections is primarily due to a combination of increased antibiotic resistance and increased 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 toxins, S. aureus strains associated with human infections can produce up to four different pore-forming bi-component leukotoxins. The long-term objective of our laboratory is to understand the molecular details by which bi-component leukotoxins influence the pathophysiology of S. aureus infection through targeting cells of the immune system. The present application focuses on one of these toxins, 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 during 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 variety of leukocytes in a receptor specific manner. The goals of this research program are to understand the mechanism by which LukED targets different leukocytes, to elucidate the consequences of LukED-mediated cell injury to S. aureus pathogenesis, and to explore the therapeutic benefits of targeting LukED as a new modality to dampen S. aureus virulence. To this end, we propose to employ a multidisciplinary approach that combines biochemistry, cell biology, and immunology techniques with ex vivo tissue culture infection models and in vivo animal models of infection. Results obtained from these studies will provide insight into the molecular details of how S. aureus bi-component pore-forming toxins selectively target and kill host cells and the importance of these toxins to S. aureus pathogenesis.