Contribution of LukED to Staphylococcus aureus pathobiology

描述（由申请人提供）：金黄色葡萄球菌是全球大量医院和社区获得性感染的原因。S.金黄色葡萄球菌感染主要是由于与社区感染相关的菌株的增加的抗生素抗性和增加的毒力的组合。在缺乏保护性疫苗的情况下，研究旨在剖析S.金黄色葡萄球菌是迫切需要的，希望确定新的目标，以产生新的治疗，以打击这种病原体。S.金黄色葡萄球菌是靶向和杀死宿主细胞的外毒素的产生。在这些毒素中，S.与人类感染相关的金黄色葡萄球菌菌株可产生多达四种不同的成孔双组分白细胞毒素。我们实验室的长期目标是了解双组分白细胞毒素影响S.金黄色葡萄球菌感染通过靶细胞的免疫系统。本申请集中于这些毒素之一，杀白细胞素艾德（Luk艾德）。这项研究的重要性源于我们最近的发现，即LukED：（i）是一个关键的毒力因子，与S.金黄色葡萄球菌血流感染，（ii）需要促进体内细菌复制，（iii）有助于S.金黄色葡萄球菌的致病机制，通过靶向和杀死体内的免疫细胞，和（iv）靶向多种白细胞的受体特异性方式。本研究的目的是了解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作为一种新的方式，以抑制S。金黄色葡萄球菌毒力。为此，我们建议采用多学科的方法，结合生物化学，细胞生物学和免疫学技术与体外组织培养感染模型和体内动物模型的感染。从这些研究中获得的结果将提供深入了解S。金黄色葡萄球菌双组分成孔毒素选择性靶向并杀死宿主细胞，以及这些毒素对金黄色葡萄球菌的重要性。金黄色葡萄球菌致病性。

DESCRIPTION (provided by applicant): 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) contribues 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.