Defective Zn Homeostasis impairs host defense against pneumococcal pneumonia

锌稳态缺陷会损害宿主对肺炎球菌肺炎的防御能力

• 批准号: 10543428
• 负责人: DAREN Lee KNOELL
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-22 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543428
• 关键词: Adaptive Immune System; Alveolar Macrophages; Bacteria; Bacterial Infections; Bacterial Pneumonia; Cell Count; Cell Lineage; Cell physiology; Cessation of life; Communication; Data; Dendritic Cells; Dietary intake; Disease; Disease susceptibility; Equilibrium; Exposure to; Functional disorder; Genetic; Goals; Homeostasis; Hospitalization; Host Defense; Hour; Human; Immune; Immune System Diseases; Immune response; Impairment; Incidence; Infection; Inflammation; Injury; Innate Immune Response; Innate Immune System; Intake; Intracellular Transport; Invaded; Investigation; Knockout Mice; Knowledge; Lung; Macrophage; Mammals; Mediating; Micronutrients; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cell Activation; Myeloid Cells; Outcome; Pathogenesis; Pathway interactions; Phagocytosis; Pilot Projects; Play; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumonia; Predisposition; Production; Public Health; Publishing; Pulmonary Inflammation; Recovery; Research; Role; Signal Pathway; Streptococcus pneumoniae; Structure of parenchyma of lung; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Vulnerable Populations; Work; ZIP protein; Zinc; Zinc deficiency; Zinc supplementation; adaptive immune response; community acquired pneumonia; cytokine; dietary; dietary restriction; disability; experience; genetic variant; immune function; improved; in vivo; loss of function; lung injury; mortality; mouse model; neutrophil; novel; novel strategies; pathogen; prevent; programs; response; risk variant; surveillance strategy; treatment strategy; uptake; zinc-binding protein

Community acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Streptococcus pneumoniae (pneumococcus) remains the most common cause of CAP in the U.S. The incidence of CAP continues to rise contributing to increased hospitalization and mortality. A major cause of CAP is decline in immune function in vulnerable populations. Zinc (Zn) is required for proper immune function and insufficient dietary intake is highly prevalent within vulnerable populations. Zn deficient subjects are more susceptible to pathogens and have a higher incidence of pneumonia whereas Zn supplementation reduces the incidence of pneumonia. The long-term goal of this project is to determine the role of the human zinc transporter ZIP8 and dietary Zn intake in the host immune response to pneumococcal pneumonia. Our group was the first to reveal that ZIP8 is required for myeloid cell activation following exposure to bacteria. This is relevant because a relative deficit of Zn, either by dietary restriction or deficits in ZIP8-mediated Zn transport, in the setting of the host response to bacterial invasion in the lung leads to immune dysfunction, increased lung damage, and higher mortality (see preliminary data). We hypothesize that ZIP8 plays a pivotal role in lung macrophages and dendritic cells by maintaining favorable balance of both the innate and adaptive immune response. Accordingly, defective Zn intake or ZIP8 function prohibits the ability of Zn to facilitate normal immune function and host defense. If proven correct, this will have important implications on pneumonia pathogenesis and increase our capacity to predict disease susceptibility and prevent morbidity and mortality. Guided by strong preliminary evidence, this hypothesis will be tested by pursuing three specific aims that will: 1) Determine the impact of ZIP8 loss on the lung myeloid landscape in vivo and its impact on pathogen clearance and host survival; 2) Determine how ZIP8 impacts Macrophage and DC function; and 3) Determine the impact of Zn supplementation on pneumococcal pneumonia in vivo in the setting of Zn dyshomeostasis. To accomplish our goals we have assembled a strong and experienced team that will pursue novel studies in two novel knockout mouse models and a model of dietary Zn restriction that will explore the role of the zinc transporter protein ZIP8 in maintaining myeloid cell-driven immune balance in the setting pneumococcal pneumonia. At the successful completion of this study, we will better understand the interplay between Zn homeostasis and ZIP8 in the context of pneumococcal infection in the lung. This is expected to have a positive impact because it will reveal previously unidentified molecular pathways that are instrumental in host defense. Further, we have the potential to identify novel micronutrient and genetic surveillance as well as treatment strategies that will improve our ability to prevent pneumococcal pneumonia in the most vulnerable populations worldwide. We envision that this will also lend itself to new approaches to treat or prevent other harmful pathogens.

社区获得的肺炎（CAP）是全球发病率和死亡率的主要原因。链球菌 肺炎（肺炎球菌）仍然是美国最常见的CAP原因 继续增加导致住院和死亡率的增加。上限的主要原因是下降 脆弱人群中的免疫功能。锌（Zn）是需要适当的免疫功能和不足的 饮食摄入量在脆弱的人群中非常普遍。锌不足的受试者更容易受到影响 病原体，肺炎发病率更高，而锌补充降低了 肺炎。该项目的长期目标是确定人类锌转运蛋白zip8和 宿主对肺炎球菌肺炎的免疫反应中的饮食锌摄入量。我们的小组是第一个揭示的人 暴露于细菌后，骨髓细胞活化是必需的。这很重要，因为亲戚 在宿主的环境中，Zn的缺陷，无论是饮食限制还是Zip8介导的Zn转运的缺陷 对肺中细菌浸润的反应会导致免疫功能障碍，肺部损伤增加，并且更高 死亡率（请参阅初步数据）。我们假设Zip8在肺巨噬细胞和树突状中起关键作用 通过维持先天和适应性免疫反应的有利平衡来保持细胞。因此，有缺陷 Zn摄入量或ZIP8功能禁止Zn促进正常免疫功能和宿主防御能力。如果 被证明是正确的，这将对肺炎发病机理具有重要意义，并增加我们的能力 预测疾病的敏感性并预防发病率和死亡率。在有力的初步证据的指导下， 假设将通过追求三个特定目标来检验：1）确定Zip8损失对 体内肺髓样景观及其对病原体清除和宿主存活的影响； 2）确定 ZIP8如何影响巨噬细胞和直流功能； 3）确定补充锌对 Zn Dyshomeostisis的体内肺炎球菌性肺炎。为了实现我们的目标 组装了一个强大而经验丰富的团队，该团队将在两个新颖的淘汰鼠标模型中进行新颖的研究 以及一种饮食锌限制的模型，将探讨锌转运蛋白Zip8的作用 粒细胞驱动的免疫平衡在设置肺炎球菌肺炎中。成功完成 这项研究，我们将更好地了解Zn稳态和Zip8之间的相互作用 肺中的肺炎球菌感染。预计这将产生积极的影响，因为它会以前揭示 在宿主防御方面发挥作用的身份不明的分子途径。此外，我们有潜力确定 新型的微量营养素和遗传监测以及治疗策略，这些策略将提高我们的预防能力 全球最脆弱的人群中的肺炎球菌肺炎。我们设想这也会借给 本身是治疗或预防其他有害病原体的新方法。