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）：二态真菌，组织囊肿（HC）是美国中西部和东南部特有的，是真菌呼吸道感染的最常见原因。该生物在巨噬细胞的细胞内环境中繁衍生息，并建立了潜在状态。使用多学科方法，包括金属蛋白质组学，免疫生物学和生物信息学，我们的研究确定了细胞因子粒细胞巨噬细胞刺激因子（GM-CSF）的新活性。人和鼠巨噬细胞暴露于GM-CSF急剧限制了锌，而不是铁或铜，可访问细胞内HC。锌的剥夺与锌进口商的明显和选择性上调有关，在鼠巨噬细胞中的两个锌出口商。此外，鼠巨噬细胞积聚了细胞内锌，但它们通过在金属硫硫代蛋白中的储存来否认它给真菌。我们已经收集了大量的机械数据，以表明限制对锌的访问是GM-CSF激活停止HC细胞内生长的主要手段。这一新发现使我们假设锌的限制是GM-CSF对巨噬细胞施加的至关重要的宿主抗性机制。在此，我们提出了3个具体目标。第一个目的是鉴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对GM-CSF做出反应，包括转运蛋白和储存分子的改变。 AIM 2利用在AIM 1和我们的初步数据中收集的数据，以调查已确定的锌转运蛋白和储存分子在剥夺HC中的功能重要性。 AIM 3将检查如何抵消GM-CSF效果的IL-4如何促进HC中锌含量的增加。该应用程序利用跨学科的团队在抗微生物效应研究和吞噬细胞生物学方面开设了有趣的远景。