Defining the molecular link between zinc deficiency and pneumonia

 描述（由申请人提供）：有大量证据表明缺锌和肺炎有关。锌是人类和细菌病原体的必需营养素，但多达三分之一的世界人口没有摄入足够的膳食锌。世界卫生组织估计，缺锌导致全球下呼吸道疾病的比例高达16%，对随机研究的汇总分析发现，补锌可使肺炎发病率降低41%。锌对于调节免疫系统是重要的，部分是通过免疫调节剂直接感应细胞内锌水平。此外，宿主免疫蛋白钙卫蛋白从细菌病原体中螯合锌，抑制它们的生长和传播。在美国，某些人群缺锌和感染条件致病菌鲍曼不动杆菌的风险增加。因为锌的获得对A.在肺炎发病过程中，我们推断它可以作为一个模型，用于定义锌缺乏增加肺炎易感性的分子机制。我们实验室的初步数据表明，缺锌显著增加了A.感染后24小时内发生鲍曼不动杆菌肺炎。该建议的中心假设是，由A.锌缺乏小鼠中的鲍曼不动杆菌肺炎是由于改变的锌体内平衡引起先天免疫应答的失调和增强的细菌毒力。该实验将整合体外和体内研究，将缺锌与A.鲍曼不动杆菌感染在特定目标1中，将分析人肺上皮细胞对A的差异反应。使用创新的高通量质谱分析平台，基于锌状态的鲍曼不动杆菌暴露。具体目标2将确定锌营养状况对A.通过宿主的元素和免疫学分析确定鲍曼不动杆菌肺炎。在具体目标3中，我们建议使用高通量转座子测序策略来鉴定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。

 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.