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.

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