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：
9405713
负责人：
Lauren Disterhoft Palmer
金额：
$ 0.14万
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/9405713
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（由应用程序提供）：有大量的证据，将缺乏锌和肺炎联系起来。对于人类和细菌病原体来说，锌是必不可少的营养素，但多达三分之一的世界人口没有足够的饮食锌。世界卫生组织估计，锌缺乏症在全球所有下呼吸道中占16％，对随机研究的合并分析发现，补充锌会使肺炎发病率降低了41％。锌对于控制免疫系统很重要，部分是通过免疫调节剂对细胞内锌水平的直接敏感性的。此外，宿主免疫蛋白钙染色蛋白会从细菌病原体中隔离锌，从而抑制其生长和传播。在美国，某些人群的锌缺乏风险和机会性病原体鲍曼尼（Baumannii）的风险增加。因为在肺炎发病机理期间，锌的采集对鲍曼尼a。我们实验室的初步数据表明，在感染后24小时内，锌缺乏可显着提高鲍曼尼肺炎肺炎肺炎的死亡率。该提议的中心假设是，锌不足小鼠中由鲍曼尼肺炎肺炎肺炎引起的死亡率是由于锌稳态改变引起的，这会导致先天免疫响应和增强细菌病毒的失调。提出的实验将整合体外和体内研究，将锌缺乏症和鲍曼尼曲霉感染引起的炎症联系起来。在特定的目标1中，将使用创新和高吞吐量质谱分析平台基于锌状态，分析人类肺上皮细胞，以根据锌状态对鲍曼尼的差异反应进行差异反应。具体目标2将通过宿主的元素和免疫学分析来确定锌营养状况对鲍曼尼肺炎曲霉的影响。在特定目标3中，我们建议使用高吞吐量转座子测序策略来鉴定对观察到的增强死亡率重要的细菌基因。这种综合方法将定义锌缺乏和肺炎之间的分子联系，并有可能显着影响我们对营养确定传染病的理解。