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.

缺锌是肺炎的主要危险因素，据估计，16%的人是由缺锌引起的 世界卫生组织在全球范围内发现的下呼吸道感染。鲍曼不动杆菌 是呼吸机相关性肺炎的主要原因，是一种极其重要的机会主义。 病原菌的多重耐药率不断上升。有风险的患者需要住院和 社区获得性鲍曼不动杆菌也增加了缺锌的风险。我们激动人心的 初步数据显示，缺锌会显著增加鲍曼不动杆菌的死亡率。 感染后24小时感染肺炎，2型细胞因子IL-13的中和具有保护作用 小鼠的死亡。这些初步数据构成了调查未知的基础 将锌缺乏与肺炎联系起来的机制将确定新的治疗靶点 锌缺乏患者肺部感染时的支持性免疫。这一点的中心假设是 有观点认为，膳食缺锌会促进肺部的II型炎症 感染，防止鲍曼不动杆菌被白细胞杀死。研究计划将确定 缺锌与肺炎之间联系的分子机制。这个 拟议的实验使用创新的多学科方法来发现潜力 多药耐药感染时提高肺天然免疫功能的治疗靶点 有机体。为确定缺锌对白细胞介导的细菌的影响 杀，我们将用高级动物来测试缺锌对白细胞功能的影响 模型和一套用于探测寄主病原体的荧光鲍曼不动杆菌 界面。此外，我们还将确定缺锌促进IL-13的机制 生产和致病作用。最后，我们将确定缺锌对小鼠的影响。 肺上皮细胞中的2型信号与鲍曼不动杆菌易位。这些目标是制定出来的 并形成我未来鉴定分子的研究计划的基础 宿主锌代谢变化影响新发疾病易感性的机制 病原菌鲍曼不动杆菌。