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

膳食缺锌对肺部感染先天免疫力的影响

• 批准号: 10478314
• 负责人: Lauren Disterhoft Palmer
• 金额: $ 8.67万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478314
• 关键词: Acinetobacter baumannii; Acinetobacter baumannii pneumonia; Affect; Animal Model; Biology; Communities; Data; Defect; Dietary Zinc; Engineering; Environmental Risk Factor; Epithelial; Hospitals; Immune; Immunity; Infection; Inflammation; Interleukin-13; Leukocytes; Link; Lower Respiratory Tract Infection; Lung; Lung infections; Mediating; Metabolism; Molecular; Multi-Drug Resistance; Mus; Natural Immunity; Pathogenicity; Patients; Pneumonia; Population; Predisposition; Production; Research; Risk; Risk Factors; Signal Transduction; Testing; World Health Organization; Zinc; Zinc deficiency; cytokine; dietary; emerging pathogen; experimental study; innovation; interdisciplinary approach; mortality; mouse model; multi-drug resistant pathogen; new therapeutic target; opportunistic pathogen; pathogen; prevent; programs; therapeutic target; ventilator-associated pneumonia

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.

锌缺乏是肺炎的主要危险因素，估计有助于16％ 世界卫生组织全球下呼吸道感染。 baumannii acinetobacter 是与呼吸机相关的肺炎的主要原因，是一个至关重要的机会主义的 病原体由于其多药电阻率上升而引起的。患有医院的风险和 社区收购的鲍曼尼（A. Baumannii）也有锌缺乏症的风险增加。我们令人兴奋 初步数据表明，锌缺乏症显着增加了鲍曼尼的死亡率 感染后24小时，肺炎，2型细胞因子IL-13的中和 来自死亡率的小鼠。这些初步数据构成了研究未知的基础 连接锌缺乏症和肺炎的机制，这些机制将确定新的治疗靶标 支持锌缺乏患者肺部感染期间的免疫力。中心假设 提议是饮食锌缺乏症会促进肺部2型炎症 感染，防止白细胞杀死鲍曼尼。研究计划将确定 锌缺乏与肺炎之间联系的分子机制。这 拟议的实验使用创新的多学科方法来发现潜力 通过耐多药物抗性促进感染期间肺部先天免疫的治疗靶标 生物。为了确定锌缺乏对白细胞介导的细菌的影响 杀人，我们将使用复杂动物测试锌缺乏对白细胞功能的影响 模型和荧光A. baumannii的工程套件，以探测宿主病原体 界面。我们还将确定锌缺乏促进IL-13的机制 生产和致病作用。最后，我们将确定Zn缺乏对 2型信号传导中的肺上皮和A. baumannii易位。这些目标是开发的 独立并构成我未来研究计划的基础，以识别分子 宿主锌代谢的变化会影响新兴的敏感性的机制 病原体A. Baumannii。