GM-CSF-Induced Metal Sequestration and Histoplasma

GM-CSF 诱导的金属螯合和组织胞浆菌

基本信息

批准号：
8660629
负责人：
GEORGE S. DEEPE
金额：
$ 50.29万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660629
关键词：
Abbreviations Acids Antifungal Agents Arachidonate 15-Lipoxygenase Bioinformatics Biology Bone Marrow Breathing Cells Cellular Immunity Cellular biology Central America Colony Stimulating Factor Activation Colony-forming units Copper Coupled Data Defense Mechanisms Deposition Environment Ethylenediamines Flow Cytometry Fluorescence Funding Generations Granulocyte Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Growth Histoplasma Histoplasma capsulatum Histoplasmosis Homeostasis Host Defense Host resistance Human Human Activities Hydroxyeicosatetraenoic Acids Immunobiology In Vitro Infection Inflammatory Response Interferon Type II Interferons Interleukin-4 Interleukins Iron Lasers Lead Lipoxygenase Lung Mass Spectrum Analysis Mediating Mediator of activation protein Metallothionein Metals Molecular Sieve Chromatography Mus Natural Immunity Nitric Oxide Organism Pathway interactions Peritoneal Phagocytes Phagosomes Physiology Plasma Polymerase Chain Reaction Prevalence Reactive Oxygen Species Recombinant Granulocyte-Macrophage Colony-Stimulating Factors Regulation Relative (related person)Research Respiratory Tract Infections Rest Reverse Transcriptase Polymerase Chain Reaction Role STAT protein Signal Pathway Signal Transduction Soil South America Southeastern United States Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Surface T-Lymphocyte Time Trace metal Up-Regulation Work Yeasts Zinc adaptive immunity antimicrobial arm chromatin immunoprecipitation combat cytokine deprivation exposed human population extracellular fungus innovation insight interdisciplinary approach ionization macrophage neutrophil novel pathogen public health relevance resistance mechanism zinc-binding protein

项目摘要

DESCRIPTION (provided by applicant): The dimorphic fungus, Histoplasma capsulatum (Hc), is endemic to the Midwestern and southeastern United States and is the most frequent cause of fungal respiratory infections. The organism thrives within the intracellular environment of macrophages and establishes a latent state. Using a multidisciplinary approach including metalloproteomics, immunobiology, and bioinformatics, our studies have identified a novel activity of the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF). Exposure of human and murine macrophages to GM-CSF sharply limits zinc, but not iron or copper, accessibility to intracellular Hc. Deprivation of zinc is associated with a marked and selective upregulation in a zinc importer and two zinc exporters in murine macrophages. Moreover, murine macrophages amass intracellular zinc but they deny it to the fungus by storage in metallothioneins. We have gathered substantial mechanistic data to indicate that limiting access to zinc is a principal means by which GM-CSF activation halts intracellular growth of Hc. This new finding has led us to hypothesize that zinc limitation is a crucial host resistance mechanism exerted by GM-CSF on macrophages. Herein, we propose 3 specific aims. The first aim is to identify the signaling pathways and zinc transporters in human macrophages that alter zinc content in host cells and in Hc. The intent is to determine how human macrophages respond to GM-CSF including alteration of transporters and storage molecules. Aim 2 harnesses data gathered in aim 1 and in our preliminary data to investigate the functional importance of the identified zinc transporters and storage molecules in depriving Hc of this trace metal. Aim 3 will examine how IL-4, which counteracts the effect of GM-CSF, promotes increases in zinc content in Hc. This application utilizes an interdisciplinary team to open an intriguing vista in antimicrobial effector research and phagocyte biology.

描述（由申请人提供）：二形性真菌，荚膜组织胞浆菌（Hc），是美国中西部和东南部的地方病，是真菌呼吸道感染的最常见原因。该生物体在巨噬细胞的细胞内环境中茁壮成长并建立潜伏状态。利用包括金属蛋白质组学、免疫生物学和生物信息学在内的多学科方法，我们的研究发现了细胞因子粒细胞巨噬细胞集落刺激因子（GM-CSF）的新活性。人类和小鼠巨噬细胞暴露于 GM-CSF 中会极大地限制锌（但不包括铁或铜）对细胞内 Hc 的可及性。锌的缺乏与小鼠巨噬细胞中一个锌输入蛋白和两个锌输出蛋白的显着且选择性上调有关。此外，小鼠巨噬细胞会积聚细胞内的锌，但它们通过储存在金属硫蛋白中而将其拒绝给真菌。我们收集了大量的机制数据表明，限制锌的获取是 GM-CSF 激活阻止 Hc 细胞内生长的主要手段。这一新发现使我们推测锌限制是 GM-CSF 对巨噬细胞施加的重要宿主抵抗机制。在此，我们提出3个具体目标。第一个目标是确定人类巨噬细胞中改变宿主细胞和 Hc 中锌含量的信号通路和锌转运蛋白。目的是确定人类巨噬细胞如何响应 GM-CSF，包括转运蛋白和储存分子的改变。目标 2 利用目标 1 中收集的数据和我们的初步数据来研究已识别的锌转运蛋白和存储分子在剥夺 Hc 这种微量金属中的功能重要性。目标 3 将研究抵消 GM-CSF 作用的 IL-4 如何促进 Hc 中锌含量的增加。该应用程序利用跨学科团队在抗菌效应器研究和吞噬细胞生物学方面开辟了有趣的前景。