GM-CSF-Induced Metal Sequestration and Histoplasma

GM-CSF 诱导的金属螯合和组织胞浆菌

• 批准号: 9256435
• 负责人: GEORGE S. DEEPE
• 金额: $ 46.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256435
• 关键词: Antifungal Agents; Arachidonate 15-Lipoxygenase; Bioinformatics; Biology; Breathing; Cells; Cellular Immunity; Cellular biology; Central America; Copper; Data; Defense Mechanisms; Deposition; Environment; Funding; Generations; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Histoplasma; Histoplasma capsulatum; Histoplasmosis; Homeostasis; Host Defense; Host resistance; Human; Human Activities; IL4 Signaling Pathway; Immunobiology; In Vitro; Infection; Inflammatory Response; Interleukin-4; Lead; Lung; MT3 gene; Macrophage Activation; Mediating; Mediator of activation protein; Metallothionein; Metals; Mus; Natural Immunity; Organism; Pathogenicity; Pathway interactions; Phagocytes; Phagosomes; Physiology; Prevalence; Recombinant Granulocyte-Macrophage Colony-Stimulating Factors; Regulation; Research; Respiratory Tract Infections; Role; Signal Pathway; Signal Transduction; Soil; South America; Southeastern United States; Surface; T-Lymphocyte; Trace metal; Up-Regulation; Work; Yeasts; Zinc; adaptive immunity; antimicrobial; arm; blocking factor; combat; cytokine; deprivation; enhancing factor; exposed human population; extracellular; fungus; innovation; insight; interdisciplinary approach; macrophage; novel; pathogen; public health relevance; resistance mechanism; zinc-binding protein

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。