Contribution of LukED to Staphylococcus aureus pathobiology

LukED 对金黄色葡萄球菌病理学的贡献

• 批准号: 8632282
• 负责人: Victor J. Torres
• 金额: $ 43.15万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632282
• 关键词: Active Immunization; Animal Model; Antibiotic Resistance; Bacteremia; Bacteria; Binding; Biochemistry; CCR5 gene; Cell Death; Cell membrane; Cells; Cellular Assay; Cellular biology; Cessation of life; Communities; Community-Acquired Infections; Conserved Sequence; Data; Dendritic Cells; Development; Exotoxins; Functional disorder; Generations; Goals; Health; Hospitals; Human; IL8RA gene; IL8RB gene; Immune; Immune system; Immunization; Immunology; Incidence; Individual; Infection; Infection Control; Injury; Laboratories; Leucocidin; Leukocytes; Libraries; Mediating; Membrane; Modality; Modeling; Molecular; Mus; Mutagenesis; Pathogenesis; Production; Research; Resistance; Role; Sepsis; Staphylococcus aureus; Surface; T memory cell; T-Lymphocyte; Targeted Toxins; Techniques; Testing; Therapeutic; Toxin; Treatment Efficacy; Vaccines; Virulence; Virulence Factors; Work; base; cell injury; cell killing; chemokine receptor; combat; cytotoxicity; in vivo; in vivo Model; inhibitor/antagonist; injured; insight; interdisciplinary approach; killings; leukotoxin; macrophage; monocyte; neutrophil; novel; novel therapeutic intervention; novel therapeutics; pathogen; prevent; programs; public health relevance; receptor; receptor binding; screening; tissue culture

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.

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 全世界。金黄色葡萄球菌感染发病率的上升主要是由于抗生素增加的综合作用 与社区感染相关的菌株的耐药性和毒力增加。在没有一个 保护性疫苗，迫切需要旨在剖析金黄色葡萄球菌毒力策略的研究 希望找到新的靶点来产生新的治疗方法来对抗这种病原体。一个 金黄色葡萄球菌的重要致病策略是产生靶向并杀死宿主细胞的外毒素。之中 这些毒素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物质 双组分白细胞毒素。我们实验室的长期目标是通过以下方式了解分子细节： 哪些双组分白细胞毒素通过靶向细胞影响金黄色葡萄球菌感染的病理生理学 免疫系统。本申请集中于这些毒素之一，杀白细胞素ED (LukED)。这 拟议研究的重要性源于我们最近的发现，LukED：（i）是一个关键 毒力因子参与金黄色葡萄球菌血流感染期间小鼠的致死，(ii) 促进体内细菌复制，(iii) 通过靶向和杀死金黄色葡萄球菌致病机制 (iv) 以受体特异性方式靶向多种白细胞。的目标 该研究计划旨在了解 LukED 靶向不同白细胞的机制， 阐明 LukED 介导的细胞损伤对金黄色葡萄球菌发病机制的影响，并探索 以 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 提议采​​用结合生物化学、细胞生物学和免疫学的多学科方法 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 这些研究将深入了解金黄色葡萄球菌双组分成孔的分子细节 毒素选择性地靶向并杀死宿主细胞以及这些毒素对金黄色葡萄球菌发病机制的重要性。