Staphylococcus aureus Survival During Nutrient Restriction and Suppression of Host Immunity.

营养限制和宿主免疫抑制期间金黄色葡萄球菌的存活。

• 批准号: 10576867
• 负责人: Francis Alonzo
• 金额: $ 46.33万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576867
• 关键词: ADP ribosylation; Affect; Anabolism; Antibiotic Resistance; Antioxidants; Bacteria; Bypass; Communities; Coupled; Dependence; Development; Disparate; Environment; Enzymes; Generations; Glycine; Goals; Grant; Growth; Homeostasis; Immune; Immune Evasion; Immune response; Immunity; Incidence; Infection; Infectious Skin Diseases; Innate Immune Response; Knowledge; Ligands; Ligase; Link; Lipids; Luciferases; Macrophage; Macrophage Activation; Mechanics; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolism; Mixed Function Oxygenases; Morbidity - disease rate; Multienzyme Complexes; Mus; NADPH Dehydrogenase; Natural Immunity; Nitrogen; Nosocomial Infections; Nutrient; Nutritional; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Oxygen; Pathway interactions; Peptides; Prevalence; Process; Production; Proteins; Public Health; Pyruvate Dehydrogenase Complex; Regulation; Resistance; Role; Sepsis; Sirtuins; Site; Skin; Staphylococcus aureus; Staphylococcus aureus infection; System; Systemic infection; TLR1 gene; Therapeutic; Thioctic Acid; Tissues; United States; Virulence; Virulent; Work; bacterial metabolism; biological adaptation to stress; cell killing; cofactor; cytokine; fitness; immune activation; improved; in vivo; intraperitoneal; mortality; mutant; new therapeutic target; novel; novel therapeutics; novel vaccines; pathogen; prevent; rational design; recruit; release factor; response; treatment strategy

Project Summary Staphylococcus aureus (Sa) is a leading cause of nosocomial infection in the United States and is a predominant pathogen in communities. Treatment of Sa infections is complicated by the prevalence of antibiotic resistant and highly virulent clones, making new therapeutic alternatives a necessity. Sa survives during infection by subverting immune defenses and adapting to host-imposed nutrient restriction. Yet, we lack a unifying understanding of these adaptations to the host environment, which complicates the development of new therapeutics and vaccines. We recently discovered that a cofactor required for metabolic enzyme complex function and potent antioxidant, lipoic acid (LA), is a critical mediator of Sa growth and survival during infection. Furthermore, we found that Sa releases the lipoylated E2 subunit of the metabolic enzyme complex pyruvate dehydrogenase to blunt protective innate immune responses via its LA moiety. Thus, our work has uncovered a mechanism of Sa survival during infection that links bacterial metabolism and nutrient acquisition to defense against innate immunity. Despite establishing these roles for LA biosynthesis and salvage in Sa pathobiology, there exist major gaps in our understanding of the mechanics of how LA blunts immunity and promotes optimal metabolism during infection. Notably: (i) the precise mechanism by which bacterial LA-protein blunts immune activation has not been elucidated; (ii) regulation of LA distribution on essential metabolic enzymes is not understood; (iii) the role of LA in mediating defense against oxidative stress has not been investigated; and (iv) the relevance of LA acquisition to survival in different infection sites is not understood. This renewal application will address these gaps in knowledge by ascertaining precisely how LA subverts immunity and the mechanics of LA synthesis/salvage that promote bacterial survival in vivo with the potential to lay the groundwork for new targeted therapeutics. Aim 1 will determine how bacterial-derived LA blunts immune responses. Aim 2 will determine how Sa regulates LA salvage and distribution. Aim 3 will investigate how accessibility to host nutrients in different tissues determines the requirement for LA during infection.

项目摘要 金黄色葡萄球菌（Sa）是美国医院感染的主要原因，并且是主要的病原体。 病原体在社区。Sa感染的治疗因抗生素耐药性的流行而复杂化， 高毒性克隆，使得新的治疗替代品成为必要。SA在感染期间存活， 破坏免疫防御并适应宿主施加的营养限制。然而，我们缺乏统一的 理解这些适应宿主环境的能力，这使得新的 治疗剂和疫苗。我们最近发现代谢酶复合物所需的辅因子 功能和有效的抗氧化剂，硫辛酸（LA），是一个关键的介质Sa的生长和生存在感染期间。 此外，我们发现Sa释放代谢酶复合物丙酮酸的脂酰化E2亚基 脱氢酶通过其LA部分钝化保护性先天免疫应答。因此，我们的工作揭示了一个 Sa在感染期间存活的机制，将细菌代谢和营养获取与防御联系起来 对抗先天免疫尽管在Sa病理生物学中确立了LA生物合成和补救的这些作用， 我们对LA如何削弱免疫力和促进最佳免疫力的机制的理解存在重大差距。 在感染过程中的代谢。值得注意的是：（i）细菌LA蛋白钝化免疫的精确机制 激活尚未阐明;（ii）LA分布对必需代谢酶的调节尚未阐明。 理解;（iii）LA在介导抗氧化应激防御中的作用尚未研究;和（iv） LA采集与不同感染部位存活率的相关性尚不清楚。这份更新申请 我将通过精确地确定LA如何破坏免疫力和免疫机制来解决这些知识上的差距。 LA合成/挽救，促进细菌在体内的存活，有可能为新的治疗奠定基础。 靶向治疗。目的1将确定细菌来源的LA如何减弱免疫反应。目标2将 确定Sa如何监管洛杉矶的回收和分配目标3将研究宿主营养素的可及性 在不同组织中的分布决定了感染期间对LA的需求。