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: 10893253
• 负责人: Victor J. Torres
• 金额: $ 55.6万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10893253
• 关键词: Amino Acids; Antibiotic Resistance; Bacteria; Biochemical; Biological; Biology; CCR5 gene; Cell membrane; Cell model; Cells; Cellular Tropism; Cellular biology; Cessation of life; Clinical; Collection; Communities; Community-Acquired Infections; Complex; Data; Development; Endothelial Cells; Endothelium; Erythrocytes; Exhibits; Exotoxins; Family; Functional disorder; Funding; Generations; Goals; Hematopoietic; Hemoglobin; Hemolysis; Hospitalization; Hospitals; Human; IL8RA gene; IL8RB gene; Immune; Immune response; Immune system; Immunology; Incidence; Infection; Iron; Leucocidin; Leukocytes; Licensing; Life Style; Methicillin; Modeling; Molecular; Multi-Drug Resistance; Mus; Pathogenesis; Pathogenicity; Patients; Phagocytes; Predisposition; Prevalence; Production; Research; Role; Sepsis; Source; Species Specificity; Staphylococcus aureus; Staphylococcus aureus infection; Structure; Targeted Toxins; Therapeutic; Time; Tissues; Toxin; Tropism; Vaccines; Virulence; Virulence Factors; Work; cell type; chemokine receptor; combat; cost; defined contribution; experimental study; humanized mouse; in vivo; information gathering; inhibitor; insight; interdisciplinary approach; methicillin resistant Staphylococcus aureus; mouse model; novel; novel therapeutics; pathogen; prevent; programs; receptor

PROJECT SUMMARY Staphylococcus aureus is responsible for a large number of hospital- and community-acquired infections worldwide. The rise in the incidence of S. aureus infections is primarily due to a combination of increased antibiotic resistance and augmented 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, S. aureus strains associated with human infections can produce up to five different pore-forming bi- component toxins known as leukocidins. The long-term objective of our program is to understand the molecular details by which these leukocidins influence the pathophysiology of S. aureus infection through targeting cells of the immune system. The present application focuses on one of these toxins as a model leukocidin, 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 upon 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 array of host cells in a receptor-dependent manner. The goals of this research program are to understand the mechanisms by which LukED targets its different host receptors, to define the details by which LukED injures endothelial cells to promote the lethality associated with bloodstream infection, and to elucidate how LukED interacts with the other leukocidins to modulate pathogenesis. To this end, we propose to employ a multidisciplinary approach that combines toxin-receptor biochemical studies with primary human cell biology and novel murine models of infection. The data gathered from these studies will provide much needed insight into the molecular details of how the bi-component leukocidins contribute to S. aureus pathobiology.

项目摘要 金黄色葡萄球菌负责大量医院和社区获得感染 全世界。金黄色葡萄球菌感染的发生率的升高主要是由于增加 与社区感染相关的菌株的抗生素耐药性和增强的毒力。在缺席的情况下 在保护性疫苗中，迫切需要旨在剖析金黄色葡萄球菌的毒力策略的研究 希望确定新的靶标，以生成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靶向和杀死宿主细胞的外毒素的产生。之中 这些，与人类感染相关的金黄色葡萄球菌菌株可产生多达五个不同的孔形成双子 成分毒素称为白细胞素。我们计划的长期目标是了解分子 这些白细胞素通过靶向细胞的细胞影响金黄色葡萄球菌感染的病理生理的细节 免疫系统。本应用的重点是这些毒素之一，作为白细胞素模型白细胞素 埃德（卢克德）。拟议研究的重要性源自我们最近发现的发现：（i）是 在金黄色葡萄球菌感染时涉及小鼠致死性的关键毒力因子（II）是需要的 在体内促进细菌复制，（iii）通过靶向和杀死免疫来促进金黄色葡萄球菌发病机理 体内细胞和（IV）以受体依赖的方式靶向多种宿主细胞。这项研究的目标 程序将了解Luked目标的机制，以定义其不同的宿主受体 卢克（Luk 并阐明Luked如何与其他白细胞素相互作用以调节发病机理。为此，我们 建议采用一种多学科方法，将毒素受体生物化学研究与主要 人类细胞生物学和新型感染模型。从这些研究中收集的数据将提供很多 需要深入了解双分量白细胞素对金黄色葡萄球菌的贡献的分子细节 病理生物学。

项目成果

SarS and Rot are necessary for the repression of lukED and lukSF-PV in Staphylococcus aureus.

• DOI: 10.1128/spectrum.01656-23
• 发表时间: 2023-12-12
• 期刊: MICROBIOLOGY SPECTRUM
• 影响因子: 3.7
• 作者: Anderson, Exene E.;Ilmain, Juliana K.;Torres, Victor J.
• 通讯作者: Torres, Victor J.