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.

社区获得性肺炎 (CAP) 是全世界发病和死亡的主要原因。链球菌属 肺炎球菌（肺炎球菌）仍然是美国 CAP 最常见的病因 CAP 的发病率 持续上升，导致住院率和死亡率增加。 CAP 的一个主要原因是 脆弱人群的免疫功能。锌 (Zn) 是正常免疫功能所必需的，但不足时 饮食摄入在弱势群体中非常普遍。缺锌的人更容易受到 病原体，肺炎的发病率较高，而补充锌可降低肺炎的发病率 肺炎。该项目的长期目标是确定人类锌转运蛋白 ZIP8 和 膳食锌摄入量影响宿主对肺炎球菌肺炎的免疫反应。我们组最先揭晓 ZIP8 是暴露于细菌后骨髓细胞激活所必需的。这是相关的，因为亲戚 在宿主环境中，由于饮食限制或 ZIP8 介导的锌转运缺陷而导致锌缺乏 对肺部细菌入侵的反应会导致免疫功能障碍，增加肺部损伤，并导致更高的死亡率 死亡率（见初步数据）。我们假设 ZIP8 在肺巨噬细胞和树突状细胞中发挥关键作用 细胞通过维持先天性和适应性免疫反应的良好平衡。据此，有缺陷的 锌摄入量或 ZIP8 功能会抑制锌促进正常免疫功能和宿主防御的能力。如果 如果被证明是正确的，这将对肺炎的发病机制产生重要影响，并提高我们的能力 预测疾病易感性并预防发病率和死亡率。在强有力的初步证据的指导下， 将通过追求三个具体目标来检验假设：1）确定 ZIP8 丢失对 体内肺髓样景观及其对病原体清除和宿主生存的影响； 2）确定 ZIP8 如何影响巨噬细胞和 DC 功能； 3) 确定补充锌对身体的影响 锌稳态失调情况下的体内肺炎球菌肺炎。为了实现我们的目标，我们有 组建了一支强大且经验丰富的团队，将在两种新型基因敲除小鼠模型中进行新颖的研究 以及饮食锌限制模型，该模型将探讨锌转运蛋白 ZIP8 在维持 肺炎球菌肺炎中骨髓细胞驱动的免疫平衡。在顺利完成时 这项研究，我们将更好地理解 Zn 稳态和 ZIP8 之间的相互作用 肺部肺炎球菌感染。预计这将产生积极影响，因为它将在之前披露 有助于宿主防御的未知分子途径。此外，我们有可能确定 新的微量营养素和基因监测以及治疗策略将提高我们预防的能力 全世界最脆弱人群中的肺炎球菌肺炎。我们预计这也将有助于 本身寻找治疗或预防其他有害病原体的新方法。