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。金黄色葡萄球菌感染发病率的上升主要是由于抗生素耐药性的增加和与社区感染相关的菌株的毒力增加的结合。在缺乏保护性疫苗的情况下，迫切需要旨在剖析金黄色葡萄球菌毒力策略的研究，以期确定新的靶点，以产生新的治疗方法来对抗这种病原体。金黄色葡萄球菌的一个重要致病策略是产生靶向并杀死宿主细胞的外毒素。在这些毒素中，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质毒素。我们实验室的长期目标是了解双组分白质毒素通过靶向免疫系统细胞影响金黄色葡萄球菌感染病理生理的分子细节。目前的应用主要集中在其中一种毒素，白细胞杀素ED （LukED）。这项研究的重要性源于我们最近的发现，LukED:(i)是金黄色葡萄球菌血流感染期间小鼠致死的关键毒力因子，（ii）是促进细菌体内复制所必需的，（iii）通过靶向和杀死体内免疫细胞来促进金黄色葡萄球菌的发病机制，（iv）以受体特异性的方式靶向多种白细胞。本研究计划的目标是了解LukED靶向不同白细胞的机制，阐明LukED介导的细胞损伤对金黄色葡萄球菌发病机制的影响，并探索LukED作为抑制金黄色葡萄球菌毒力的新方式的治疗益处。为此，我们建议采用多学科方法，将生物化学、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感染动物模型相结合。从这些研究中获得的结果将深入了解金黄色葡萄球菌双组分成孔毒素如何选择性靶向和杀死宿主细胞的分子细节，以及这些毒素对金黄色葡萄球菌发病机制的重要性。

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.