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罪魁祸首。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毒力的增加。在缺乏保护性疫苗的情况下，迫切需要研究金黄色葡萄球菌的毒力策略，希望为抗击这种病原体的新疗法的产生找到新的靶点。金黄色葡萄球菌的一个重要致病策略是产生以宿主细胞为靶标并杀死宿主细胞的外毒素。在这些毒素中，与人类感染有关的金黄色葡萄球菌菌株可以产生多达四种不同的形成毛孔的双组分白细胞毒素。我们实验室的长期目标是了解双组分白毒素通过靶向免疫系统的细胞而影响金黄色葡萄球菌感染的病理生理学的分子细节。本申请的重点是其中一种毒素--杀白素ED(LukED)。这项拟议研究的重要性源于我们最近的发现：(I)LukED是金黄色葡萄球菌血流感染过程中小鼠致死的关键毒力因子，(Ii)在体内促进细菌复制所必需的，(Iii)在体内通过靶向和杀死免疫细胞而促成金黄色葡萄球菌的发病，以及(Iv)以受体特异性的方式针对多种白细胞。本研究的目标是了解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致病的影响，并探索靶向LukED作为一种新的方式抑制金黄色葡萄球菌毒力的治疗效果。为此，我们建议采用生物化学、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感染模型相结合的多学科方法。这些研究的结果将为深入了解金黄色葡萄球菌双组分成孔毒素如何选择性地靶向和杀死宿主细胞以及这些毒素在金黄色葡萄球菌致病机制中的重要性提供分子细节。

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.