Metallobiochemistry of innate immunity and bacterial physiology

先天免疫的金属生物化学和细菌生理学

基本信息

项目摘要

PROJECT SUMMARY The primary objective of this renewal application is to elucidate how the metal-sequestering host-defense protein calprotectin (CP) modulates the physiology and interactions of Pseudomonas aeruginosa (Pa) and Staphylococcus aureus (Sa) using models that consider environmental cues relevant to infection. Metal ions are essential nutrients for all organisms, and pathogens must acquire these nutrients from the host to replicate and cause infection. In response to pathogen invasion, the human innate immune system enacts a metal- withholding response to limit the bioavailability of transition metal nutrients including manganese (Mn), iron (Fe), and zinc (Zn). This host response includes the deployment of CP and other metal-sequestering proteins at sites of infection. We discovered that CP withholds Fe(II) from and induces Fe-starvation responses by Pa and Sa, two bacterial pathogens that cause chronic polymicrobial infections in diverse patient populations, including lung infections in individuals with cystic fibrosis (CF). This hereditary disease predisposes individuals to life-long pulmonary infections, marked by debilitating exacerbations that reduce lung function. Notably, the CF lung becomes increasingly acidic and hypoxic as disease progresses, and Fe(II) becomes a predominant form of bioavailable Fe in this environment. Nevertheless, few studies have addressed how acidic pH and hypoxia impact microbial Fe homeostasis and the host metal-withholding response. We hypothesize that the Fe(II)-sequestering activity of CP has profound consequences on the physiology and virulence potential of Pa and Sa in diverse environmental milieus relevant to infection. We further propose that interactions between CP and these pathogens depend on environmental cues that vary both temporally and spatially at infection foci. In Aim 1, we will evaluate how mildly-acidic pH affects the metal-sequestration profile of CP as well as the physiology of Pa and Sa and their responses to CP and metal starvation. In Aim 2, we will examine how hypoxia affects the responses of Pa and Sa to metal starvation and CP. In Aim 3, we will extend these investigations to more complex in vitro models that incorporate relevant aspects of infection including co- cultures, biofilms, and additional metal-sequestering host-defense factors such as lactoferrin and S100A12. These investigations will enable future studies that address how CP and Fe drive the progression of CF lung infections and may guide the design and development of novel diagnostic, preventative, and therapeutic approaches to treat bacterial infections.
项目摘要 这项更新申请的主要目的是阐明金属螯合宿主防御是如何 蛋白质钙卫蛋白(CP)调节铜绿假单胞菌(Pa)的生理和相互作用, 金黄色葡萄球菌(Sa)使用考虑与感染相关的环境线索的模型。金属离子 是所有生物体的必需营养素,病原体必须从宿主那里获得这些营养素才能复制 导致感染为了应对病原体入侵,人类先天免疫系统会产生一种金属- 抑制反应以限制过渡金属营养物的生物利用度,包括锰(Mn)、铁 (Fe)和锌(Zn)。这种宿主反应包括CP和其他金属螯合蛋白的部署 在感染部位。我们发现,CP抑制Fe(II),并诱导铁饥饿反应的Pa 和Sa,两种在不同患者群体中引起慢性多种微生物感染的细菌病原体, 包括囊性纤维化(CF)患者的肺部感染。这种遗传性疾病使个体 终身肺部感染,其特征是使人衰弱的恶化,降低肺功能。特别是 随着疾病的进展,CF肺变得越来越酸性和缺氧,并且Fe(II)成为主要的 在这种环境中生物可利用的铁的形式。然而,很少有研究讨论了酸性pH值和 缺氧影响微生物Fe稳态和宿主金属抑制反应。我们假设 CP的Fe(II)螯合活性对Pa的生理和毒性潜力具有深远的影响 和Sa在不同环境中与感染有关。我们进一步提出,CP之间的相互作用 并且这些病原体依赖于在感染病灶处时间和空间上变化的环境线索。在 目的1,我们将评估弱酸性pH如何影响CP的金属螯合概况以及 Pa和Sa的生理特性以及它们对CP和金属饥饿的反应。在目标2中,我们将研究如何 低氧影响Pa和Sa对金属饥饿和CP的反应。在目标3中,我们将扩展这些 研究更复杂的体外模型,包括感染的相关方面, 培养物、生物膜和额外的金属螯合宿主防御因子如乳铁蛋白和S100 A12。 这些研究将使未来的研究能够解决CP和Fe如何驱动CF肺的进展 感染,并可能指导设计和开发新的诊断,预防和治疗 治疗细菌感染的方法。

项目成果

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ELIZABETH M NOLAN其他文献

ELIZABETH M NOLAN的其他文献

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{{ truncateString('ELIZABETH M NOLAN', 18)}}的其他基金

Harnessing iron acquisition to hinder enterobacterial pathogenesis
利用铁的获取来阻碍肠细菌的发病机制
  • 批准号:
    10651432
  • 财政年份:
    2023
  • 资助金额:
    $ 33.43万
  • 项目类别:
Antimicrobial activity of Escherichia coli Nissle 1917 microcin M
大肠杆菌 Nissle 1917 microcin M 的抗菌活性
  • 批准号:
    10212238
  • 财政年份:
    2020
  • 资助金额:
    $ 33.43万
  • 项目类别:
Metallobiochemistry of innate immunity and bacterial physiology
先天免疫的金属生物化学和细菌生理学
  • 批准号:
    9436092
  • 财政年份:
    2017
  • 资助金额:
    $ 33.43万
  • 项目类别:
Bioinorganic Explorations of Host-Defense Proteins
宿主防御蛋白的生物无机探索
  • 批准号:
    9982335
  • 财政年份:
    2017
  • 资助金额:
    $ 33.43万
  • 项目类别:
Bioinorganic Explorations of Host-Defense Proteins
宿主防御蛋白的生物无机探索
  • 批准号:
    9239551
  • 财政年份:
    2017
  • 资助金额:
    $ 33.43万
  • 项目类别:
Bioinorganic Explorations of Host-defense Proteins
宿主防御蛋白的生物无机探索
  • 批准号:
    10530840
  • 财政年份:
    2017
  • 资助金额:
    $ 33.43万
  • 项目类别:
Bioinorganic Explorations of Host-Defense Proteins
宿主防御蛋白的生物无机探索
  • 批准号:
    9752605
  • 财政年份:
    2017
  • 资助金额:
    $ 33.43万
  • 项目类别:
Bioinorganic Explorations of Host-defense Proteins
宿主防御蛋白的生物无机探索
  • 批准号:
    10662538
  • 财政年份:
    2017
  • 资助金额:
    $ 33.43万
  • 项目类别:
Metallobiochemistry of innate immunity and bacterial physiology
先天免疫的金属生物化学和细菌生理学
  • 批准号:
    10468860
  • 财政年份:
    2017
  • 资助金额:
    $ 33.43万
  • 项目类别:
Metallobiochemistry of innate immunity and bacterial physiology
先天免疫的金属生物化学和细菌生理学
  • 批准号:
    10686285
  • 财政年份:
    2017
  • 资助金额:
    $ 33.43万
  • 项目类别:

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