Defining the molecular link between zinc deficiency and pneumonia

定义缺锌与肺炎之间的分子联系

基本信息

项目摘要

 DESCRIPTION (provided by applicant): There is a large body of evidence linking zinc deficiency and pneumonia. Zinc is an essential nutrient for both humans and bacterial pathogens, but up to one third of the world population does not consume sufficient dietary zinc. The World Health Organization has estimated that zinc deficiency contributes to up to 16% of all lower respiratory globally, and a pooled analysis of randomized studies found that zinc supplementation reduced pneumonia incidence by 41%. Zinc is important for regulating the immune system, partly through direct sensing of intracellular zinc levels by immunoregulators. Additionally, the host immune protein calprotectin sequesters zinc from bacterial pathogens, suppressing their growth and dissemination. In the United States, certain populations are at increased risk for zinc deficiency and infection by the opportunistic pathogen Acinetobacter baumannii. Because zinc acquisition is critical to A. baumannii during pneumonia pathogenesis, we reasoned that it could serve as a model for defining the molecular mechanisms by which zinc deficiency increases pneumonia susceptibility. Preliminary data from our laboratory demonstrated that zinc deficiency significantly increases mortality from A. baumannii pneumonia by 24 hours post infection. The central hypothesis of this proposal is that mortality caused by A. baumannii pneumonia in zinc deficient mice is due to altered zinc homeostasis, which causes dysregulation of the innate immune response and enhanced bacterial virulence. The experiments proposed will integrate in vitro and in vivo studies linking zinc deficiency and inflammation caused by A. baumannii infection. In Specific Aim 1, human lung epithelial cells will be analyzed for differential responses to A. baumannii exposure based on zinc status using an innovative and high throughput mass spectrometry assay platform. Specific Aim 2 will determine the effect of zinc nutritional status on A. baumannii pneumonia by elemental and immunological analysis of the host. In Specific Aim 3, we propose to identify bacterial genes important for the observed enhanced mortality using a high throughput transposon sequencing strategy. This integrated approach will define molecular links between zinc deficiency and pneumonia and has the potential to significantly impact our understanding of nutritional determinants of infectious disease.
 描述(申请人提供):有大量证据表明缺锌与肺炎有关。锌是人类和细菌病原体的基本营养素,但世界上多达三分之一的人口没有摄入足够的膳食锌。世界卫生组织估计,在全球所有下呼吸道疾病中,锌缺乏的比例高达16%,一项随机研究的汇集分析发现,补锌可将肺炎的发病率降低41%。锌对调节免疫系统很重要,部分是通过免疫调节剂直接检测细胞内锌水平来实现的。此外,宿主免疫蛋白钙保护素将锌从细菌病原体中隔离出来,抑制它们的生长和传播。在美国,某些人群患锌缺乏和感染鲍曼不动杆菌的风险增加。由于锌的获得在肺炎发病机制中对鲍曼不动杆菌至关重要,我们推测它可以作为一个模型来确定缺锌增加肺炎易感性的分子机制。我们实验室的初步数据显示,在感染后24小时内,缺锌会显著增加鲍曼不动杆菌肺炎的死亡率。这一建议的中心假设是,鲍曼不动杆菌肺炎导致缺锌小鼠的死亡是由于锌稳态的改变,这导致了天然免疫反应的失调和细菌毒力的增强。拟议的实验将整合体内和体外的研究,将缺锌和鲍曼不动杆菌感染引起的炎症联系起来。在具体目标1中,将使用创新的高通量质谱分析平台,分析人肺上皮细胞对鲍曼不动杆菌暴露的不同反应,基于锌状态。目的2通过对宿主的元素分析和免疫学分析,确定锌营养状况对鲍曼不动杆菌肺炎的影响。在具体目标3中,我们建议使用高通量转座子测序策略来识别对观察到的死亡率增加重要的细菌基因。这一综合方法将确定缺锌和肺炎之间的分子联系,并有可能显著影响我们对传染病营养决定因素的理解。

项目成果

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Lauren Disterhoft Palmer其他文献

Lauren Disterhoft Palmer的其他文献

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{{ truncateString('Lauren Disterhoft Palmer', 18)}}的其他基金

The impact of dietary zinc deficiency on innate immunity to lung infection
膳食缺锌对肺部感染先天免疫力的影响
  • 批准号:
    10327646
  • 财政年份:
    2021
  • 资助金额:
    $ 5.71万
  • 项目类别:
The impact of dietary zinc deficiency on innate immunity to lung infection
膳食缺锌对肺部感染先天免疫力的影响
  • 批准号:
    10764457
  • 财政年份:
    2021
  • 资助金额:
    $ 5.71万
  • 项目类别:
The impact of dietary zinc deficiency on innate immunity to lung infection
膳食缺锌对肺部感染先天免疫力的影响
  • 批准号:
    10557920
  • 财政年份:
    2021
  • 资助金额:
    $ 5.71万
  • 项目类别:
The impact of dietary zinc deficiency on innate immunity to lung infection
膳食缺锌对肺部感染先天免疫力的影响
  • 批准号:
    10294382
  • 财政年份:
    2021
  • 资助金额:
    $ 5.71万
  • 项目类别:
The impact of dietary zinc deficiency on innate immunity to lung infection
膳食缺锌对肺部感染先天免疫力的影响
  • 批准号:
    10478314
  • 财政年份:
    2021
  • 资助金额:
    $ 5.71万
  • 项目类别:
The impact of dietary zinc deficiency on innate immunity to lung infection
膳食缺锌对肺部感染先天免疫力的影响
  • 批准号:
    10836257
  • 财政年份:
    2021
  • 资助金额:
    $ 5.71万
  • 项目类别:
The impact of dietary zinc deficiency on innate immunity to lung infection
膳食缺锌对肺部感染先天免疫力的影响
  • 批准号:
    10005451
  • 财政年份:
    2019
  • 资助金额:
    $ 5.71万
  • 项目类别:
Defining the molecular link between zinc deficiency and pneumonia
定义缺锌与肺炎之间的分子联系
  • 批准号:
    9405713
  • 财政年份:
    2016
  • 资助金额:
    $ 5.71万
  • 项目类别:

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用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
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