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

批准号：
9269054
负责人：
Lauren Disterhoft Palmer
金额：
$ 5.71万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269054
关键词：
A549 Acinetobacter baumannii Affect Animal Model Antimicrobial Effect Bacterial Genes Bacterial Pneumonia Biological Assay Cell model Cells Cessation of life Child Clinical Communicable Diseases Data Dendritic Cells Dietary Zinc Epidemiology Epithelial Cells Genes Growth Health Homeostasis Hour Human Immune Immune system Immunization Immunologics In Vitro Incidence Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Intensive Care Units Laboratories Leukocyte L1 Antigen Complex Life Link Lipopolysaccharides Lung Mass Spectrum Analysis Mediator of activation protein Metabolism Metals Modeling Molecular Mus Natural Immunity Nosocomial Infections Nutrient Nutritional Nutritional status Opportunistic Infections Outcome Pathogenesis Pathology Patients Phenotype Play Pneumonia Population Predisposition Prevention Process Proteins Randomized Randomized Controlled Trials Recruitment Activity Reporting Respiratory physiology Risk Role Sepsis Site Testing Time Tissues Total Parenteral Nutrition Translational Research United States Virulence Work World Health Organization Zinc Zinc deficiency Zinc supplementation adaptive immune response antimicrobial peptide base chelation cytokine experimental study genome-wide immune function improved in vitro Assay in vivo innate immune function innovation mortality mouse model neutrophil novel nutrition older patient pathogen public health relevance respiratory response ventilator-associated pneumonia zinc-binding protein

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（由申请人提供）：有大量证据表明锌缺乏与肺炎有关，锌是人类和细菌病原体的必需营养素，但世界上多达三分之一的人口没有摄入足够的膳食锌。卫生组织估计，全球下呼吸道患者缺锌的比例高达 16%，随机研究的汇总分析发现，补充锌可将肺炎发病率降低 41%，锌对于调节免疫系统非常重要，部分是通过直接作用实现的。传感此外，宿主免疫蛋白钙卫蛋白可隔离细菌病原体中的锌，抑制其生长和传播。在美国，某些人群缺锌和被机会性病原体鲍曼不动杆菌感染的风险增加。获得对于鲍曼不动杆菌在肺炎发病机制中至关重要，我们推断它可以作为定义锌缺乏增加肺炎易感性的分子机制的模型。我们实验室的初步数据表明，感染后 24 小时内，锌缺乏会显着增加鲍曼不动杆菌肺炎的死亡率。该提议的中心假设是，缺锌小鼠中鲍曼不动杆菌肺炎引起的死亡是由于锌稳态改变所致。导致先天免疫反应失调和细菌毒力增强。具体目标 1 中，人肺中的实验将整合锌缺乏与鲍曼不动杆菌感染引起的炎症之间的联系。将使用创新的高通量质谱分析平台，根据锌状态分析上皮细胞对鲍曼不动杆菌暴露的差异反应。具体目标 2 将通过元素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，这种综合方法将确定锌缺乏和肺炎之间的分子联系，并有可能产生重大影响。我们对传染病营养决定因素的理解。