The impact of dietary zinc deficiency on innate immunity to lung infection

锌缺乏是肺炎的主要危险因素，据估计， 下呼吸道感染的全球范围内，世界卫生组织。鲍曼不动杆菌 是呼吸机相关性肺炎的主要原因， 病原体由于其多药耐药性的上升率。有住院风险的患者， 社区获得了A.鲍曼不动杆菌也会增加缺锌的风险。整理的丰厚 初步数据显示，缺锌显著增加了A.鲍曼不 感染后24小时，中和2型细胞因子IL-13可保护 小鼠死亡。这些初步数据构成了调查未知事物的基础 将锌缺乏和肺炎联系起来的机制，将确定新的治疗靶点， 在缺锌患者肺部感染期间支持免疫。这个问题的核心假设是 建议是饮食锌缺乏促进肺2型炎症， 感染，预防A.白细胞对鲍曼不动杆菌的杀伤作用。研究计划将确定 锌缺乏和肺炎之间联系的分子机制。的 拟议的实验使用创新的多学科方法来揭示潜在的 治疗靶点，以促进肺先天免疫在感染期间由多药耐药 有机体为了确定锌缺乏对白细胞介导的细菌感染的影响， 杀，我们将测试锌缺乏对白细胞功能的影响，使用先进的动物 模型和一套荧光A.鲍曼不动杆菌探测宿主病原体 接口.我们将进一步确定锌缺乏促进IL-13的机制。 生产和致病作用。最后，我们将确定锌缺乏对 肺上皮中的2型信号和A.鲍曼不动杆菌易位这些目标是 独立，并形成我未来研究计划的基础，以确定分子 宿主锌代谢的变化影响对新出现的 病原体A.鲍曼不动杆菌。

Zinc deficiency is a major risk factor for pneumonia, and is estimated to contribute to 16% of lower respiratory infections globally by the World Health Organization. Acinetobacter baumannii is a leading cause of ventilator associated pneumonia and is a critically important opportunistic pathogen due to its rising rates of multi-drug resistance. Patients at risk for hospital and community acquired A. baumannii are also at increased risk of zinc deficiency. Our exciting preliminary data show that zinc deficiency significantly increases mortality from A. baumannii pneumonia by 24 h post infection, and that neutralization of the type 2 cytokine IL-13 protects mice from mortality. These preliminary data form the basis of investigating the unknown mechanisms linking zinc deficiency and pneumonia that will identify new therapeutic targets to support immunity during lung infection of zinc deficient patients. The central hypothesis of this proposal is that dietary Zn deficiency promotes type 2 inflammation during lung infection, preventing A. baumannii killing by leukocytes. The research plan will identify molecular mechanisms underlying the link between zinc deficiency and pneumonia. The proposed experiments use an innovative multi-disciplinary approach to uncover potential therapeutic targets to promote lung innate immunity during infection by a multi-drug resistant organism. In order to determine the effect of Zn deficiency on leukocyte-mediated bacterial killing, we will test the effect of zinc deficiency on leukocyte function using sophisticated animal models and an engineered suite of fluorescent A. baumannii to probe the host-pathogen interface. We will additionally identify the mechanism by which Zn deficiency promotes IL-13 production and pathogenic effects. Finally, we will determine the effect of Zn deficiency on the lung epithelium in type 2 signaling and A. baumannii translocation. These aims were developed independently and form the basis of my future research program to identify the molecular mechanisms by which changes in host zinc metabolism affect susceptibility to the emerging pathogen A. baumannii.