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:
    10368013
  • 负责人:
  • 金额:
    $ 4.46万
  • 依托单位:
  • 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 2022-07-31
  • 项目状态:
    已结题

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.
项目摘要 金黄色葡萄球菌(Sa)是美国医院感染的主要原因,也是主要的 社区中的病原体。沙门氏菌感染的治疗因抗生素耐药和 高毒力的克隆,使新的治疗选择成为必要。SA在感染期间存活下来 颠覆免疫防御,适应寄主施加的营养限制。然而,我们缺乏一个统一的 了解这些对宿主环境的适应,这使新的 治疗学和疫苗。我们最近发现了一种代谢酶复合体所需的辅因子 硫辛酸(LA)是一种功能强大的抗氧化剂,是沙门氏菌在感染期间生长和存活的关键介质。 此外,我们还发现Sa释放代谢酶复合体丙酮酸的脂基化的E2亚单位。 脱氢酶通过其LA部分钝化保护性先天免疫反应。因此,我们的工作揭示了一个 细菌新陈代谢和营养获取与防御有关的感染期间沙门氏菌存活机制 对抗先天免疫力。尽管在SA病理生物学中为LA的生物合成和回收建立了这些角色, 在我们对洛杉矶如何钝化免疫力和促进最佳免疫的机制的理解上存在重大差距 感染期间的新陈代谢。值得注意的是:(I)细菌LA蛋白钝化免疫的确切机制 激活尚未阐明;(Ii)LA在必需代谢酶上的分布调节尚不清楚 了解;(Iii)LA在介导对氧化应激的防御中的作用尚未被研究;和(Iv) LA的获得性与在不同感染部位存活的相关性尚不清楚。此续期申请 将通过准确地确定LA如何颠覆免疫力和 促进细菌在体内存活的LA合成/挽救,有可能为新的 靶向治疗。目标1将确定细菌来源的LA如何钝化免疫反应。目标2将 确定SA如何管理LA的打捞和分配。目标3将调查宿主营养素的可及性 在不同的组织中,决定了感染过程中对LA的需求。

项目成果

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会议论文数量(0)
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Francis Alonzo其他文献

Francis Alonzo的其他文献

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{{ truncateString('Francis Alonzo', 18)}}的其他基金

2022 International Conference on Gram Positive Pathogens
2022年革兰氏阳性病原体国际会议
  • 批准号:
    10539629
  • 财政年份:
    2022
  • 资助金额:
    $ 4.46万
  • 项目类别:
Intercellular Communication and Pheromone Maturation in Gram-Positive Bacteria.
革兰氏阳性细菌的细胞间通讯和信息素成熟。
  • 批准号:
    10153696
  • 财政年份:
    2020
  • 资助金额:
    $ 4.46万
  • 项目类别:
Intercellular Communication and Pheromone Maturation in Gram-Positive Bacteria.
革兰氏阳性细菌的细胞间通讯和信息素成熟。
  • 批准号:
    10388364
  • 财政年份:
    2020
  • 资助金额:
    $ 4.46万
  • 项目类别:
Intercellular Communication and Pheromone Maturation in Gram-Positive Bacteria.
革兰氏阳性细菌的细胞间通讯和信息素成熟。
  • 批准号:
    10616714
  • 财政年份:
    2020
  • 资助金额:
    $ 4.46万
  • 项目类别:
Intercellular Communication and Pheromone Maturation in Gram-Positive Bacteria.
革兰氏阳性细菌的细胞间通讯和信息素成熟。
  • 批准号:
    10025778
  • 财政年份:
    2020
  • 资助金额:
    $ 4.46万
  • 项目类别:
Intercellular Communication and Pheromone Maturation in Gram-Positive Bacteria.
革兰氏阳性细菌的细胞间通讯和信息素成熟。
  • 批准号:
    10634044
  • 财政年份:
    2020
  • 资助金额:
    $ 4.46万
  • 项目类别:
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:
    10047411
  • 财政年份:
    2016
  • 资助金额:
    $ 4.46万
  • 项目类别:
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
  • 财政年份:
    2016
  • 资助金额:
    $ 4.46万
  • 项目类别:
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:
    10634196
  • 财政年份:
    2016
  • 资助金额:
    $ 4.46万
  • 项目类别:
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:
    9121678
  • 财政年份:
    2016
  • 资助金额:
    $ 4.46万
  • 项目类别:

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