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。

基本信息

批准号：
10047411
负责人：
Francis Alonzo
金额：
$ 44.59万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
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/10047411
关键词：
ADP ribosylation Address Affect Anabolism Antibiotic Resistance Antioxidants Bacteria Bypass Communities Coupled Dependence Development Environment Enzymes Generations Glycine Goals Grant Growth Homeostasis Immune Immune response Immunity Incidence Infection Infectious Skin Diseases Innate Immune Response Knowledge Ligands Ligase Link Lipids Luciferases Macrophage Activation Mechanics Mediating Mediator of activation protein 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 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 design fitness immune activation improved in vivo intraperitoneal macrophage mortality mutant new therapeutic target novel novel therapeutics novel vaccines pathogen prevent recruit release factor response treatment strategy

项目摘要

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.

项目概要金黄色葡萄球菌 (Sa) 是美国医院内感染的主要原因，也是主要的致病菌社区中的病原体。 Sa 感染的治疗因抗生素耐药性和耐药性的普遍存在而变得复杂高毒力的克隆，使得新的治疗替代方案成为必要。 Sa在感染期间存活下来破坏免疫防御并适应宿主施加的营养限制。然而，我们缺乏一个统一的了解这些对宿主环境的适应，这使得新的开发变得复杂疗法和疫苗。我们最近发现代谢酶复合物所需的辅因子硫辛酸 (LA) 具有功能和有效的抗氧化剂，是感染期间 Sa 生长和存活的关键介质。此外，我们发现 Sa 释放代谢酶复合物丙酮酸的硫辛酸化 E2 亚基脱氢酶通过其 LA 部分减弱保护性先天免疫反应。因此，我们的工作揭示了一个 Sa在感染期间的生存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 病理学中确立了 LA 生物合成和挽救的这些作用，我们对 LA 如何削弱免疫力和促进最佳状态的机制的理解存在重大差距感染期间的新陈代谢。值得注意的是：(i) 细菌 LA 蛋白削弱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不是明白了； (iii) LA 在介导氧化应激防御中的作用尚未得到研究； (四) LA 获得与不同感染部位生存的相关性尚不清楚。本次续签申请将通过准确确定洛杉矶如何破坏免疫力以及其机制来解决这些知识空白 LA 合成/回收可促进细菌在体内的存活，并有可能为新的药物奠定基础靶向治疗。目标 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 LA 的回收和分配。目标 3 将研究宿主营养物质的可及性不同的组织决定了感染期间对 LA 的需求。