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（由申请人证明）：有很多证据是锌不足的肺炎和细菌病原体。在全球所有下呼吸道中，有16％的随机d研究发现，锌使肺炎发病率降低了41％。锌病的风险增加感染后24小时，肺炎是由A.引起的。 A.在特定的目标中，使用创新和高吞吐量质量光谱法的人类肺部将分析对baumannii的差异反应。 A.宿主的分析。我们对传染病的营养决定因素的理解。