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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

基本信息

批准号：
10365619
负责人：
DAREN Lee KNOELL
金额：
$ 38.3万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10365619
关键词：
Adaptive Immune System Alveolar Macrophages Bacteria Bacterial Infections Bacterial Pneumonia Carrier Proteins Cell Count Cell Lineage Cell physiology Cessation of life Communication Data Dendritic Cells Dietary Zinc 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 Intake Intracellular Transport Investigation Knockout Mice Knowledge Lung 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 Zinc Zinc deficiency Zinc supplementation adaptive immune response base community acquired pneumonia cytokine dietary dietary restriction disability experience genetic variant immune function improved in vivo loss of function lung injury macrophage mortality mouse model neutrophil novel novel strategies pathogen prevent programs response risk variant surveillance strategy treatment strategy uptake zinc-binding protein

项目摘要

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）是世界范围内发病率和死亡率的主要原因。链球菌