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: 9976977
• 负责人: GEORGE S. DEEPE
• 金额: $ 53.1万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976977
• 关键词: Area; Binding; Bioinformatics; Biological; Biology; Cathepsins; Cell membrane; Cells; Cellular biology; Central America; Colony Stimulating Factor Activation; Colony-Stimulating Factors; Cytokine Activation; Data; Dendritic Cells; Deposition; Environment; Enzymes; Exhibits; Funding; Genotype; Glycolysis; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Histoplasma; Histoplasma capsulatum; Homeostasis; Host Defense; Human; Immune; Immune response; Immunology; Infection; Interferons; Interleukin-4; Investigation; Knowledge; Link; Lung; MT3 gene; Mediating; Mediator of activation protein; Membrane; Metabolic; Metabolism; Metalloproteins; Metallothionein; Metals; Molds; Mus; Mycoses; Organism; PF4 Gene; Pathogenicity; Phagocytes; Phagosomes; Phase; Phenotype; Physiology; Planet Earth; Prevalence; Production; Property; Proteome; Reactive Oxygen Species; Regulation; Reproduction spores; Role; Shapes; Soil; South America; T-Lymphocyte; Trace metal; Vacuole; Work; Yeasts; Zinc; adaptive immune response; combat; cytokine; deprivation; design; extracellular; fungus; granulocyte; immunoregulation; in vivo; insight; interdisciplinary approach; macrophage; metabolic phenotype; microbial disease; monocyte; novel; novel strategies; pathogenic fungus; prevent; respiratory; response; stressor; transcription factor; zinc thionein; zinc-binding protein

The pathogenic fungus, Histoplasma capsulatum, is endemic to the Midwestern and Southeastern US and is the most frequent cause of respiratory fungal infection. The organism thrives within the intracellular environ- ment of monocytes (Mo) and macrophages (Mɸ) and has the capacity to establish a latent state. Employing a multidisciplinary approach including metallomics, immunology, cell biology and bioinformatics, our studies have identified novel functions of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 that help to explain their disparate effects on the growth of the fungus with Mo/Mɸ. GM-CSF deprives the organism of zinc intracellularly while concurrently boosting production of reactive oxygen species. The end result is killing of yeast cells. On the other hand, IL-4 promotes intracellular survival by fortifying the amount of zinc available to Histoplasma. Crucial to the activities of GM-CSF and IL-4 are metallothioneins (MTs), which store and donate zinc, and zinc transporters. They are a central node mediating the link between cytokine activation and effector function. For GM-CSF, MTs1 & 2 are essential whereas for IL-4, it is MT3. In this proposal, we will build on our work conducted during the last funding cycle and explore in depth how the MT- zinc axis regulates the activity of GM-CSF and IL-4 on human and mouse Mo/Mɸ. We have collected exciting data that glycolysis governs the expression of MTs1&2 in infected GM-CSF-stimulated Mo/Mɸ. On the other hand, MT3 tempers the glycolytic response in IL-4 activated in these cells. Aim 1 will decipher how glycolysis molds MT1&2 expression and intracellular Zn2+ distribution to bolster Mo/Mɸ effector function. Aim 2 will define the intracellular alterations in GM-CSF-activated Mo/Mɸ that deny the fungus access to zinc and the in vivo effect of MTs1&2 on host defenses exerted by these phagocytes. Aim 3 will elucidate the intersection of glycolysis and MT3 in shaping the physiology of IL-4 on Histoplasma-infected Mo/Mɸ. These studies will provide new insights into cytokine regulation of metabolism and metallobiology in Histoplasma-infected Mo/Mɸ.

致病真菌，组织胞浆菌，是美国中西部和东南部的地方病， 是呼吸道真菌感染最常见的原因。有机体在 单核细胞（Mo）和巨噬细胞（M β）的细胞内环境，并具有 建立一个潜在的国家。采用多学科方法，包括金属组学，免疫学， 细胞生物学和生物信息学，我们的研究已经确定了新的功能，粒细胞 巨噬细胞集落刺激因子（GM-CSF）和白细胞介素（IL）-4有助于解释其 钼/钼比值对真菌生长的影响不同。GM-CSF剥夺机体的锌 在细胞内同时促进活性氧物质的产生。最终的结果 是杀死酵母细胞 另一方面，IL-4通过强化细胞内的细胞因子， 组织胞浆菌可利用的锌量。GM-CSF和IL-4活性的关键是 金属硫蛋白（MT），其储存和提供锌，以及锌转运蛋白。它们是一个中心节点 介导细胞因子活化和效应子功能之间的联系。对于GM-CSF，MT 1和2是 而对于IL-4，它是MT3。在本提案中，我们将以我们在2010年期间开展的工作为基础， 最后一个资金周期，并深入探讨MT-锌轴如何调节GM-CSF的活性 和IL-4对人和小鼠Mo/M β的影响。我们已经收集了令人兴奋的数据，糖酵解控制着 在感染的GM-CSF刺激的Mo/M β中MTs 1和MTs 2的表达。另一方面，MT3缓和了 这些细胞中IL-4的糖酵解反应被激活。目标1将破译糖酵解如何塑造 MT 1和2表达和细胞内Zn 2+分布以支持Mo/M β效应器功能。 目的2 将定义GM-CSF激活的Mo/M受体的细胞内改变，其拒绝真菌进入 锌和MTs 1和2对这些吞噬细胞发挥的宿主防御的体内作用。目标3将 阐明糖酵解和MT3在形成IL-4生理学中的交叉点， 组织胞浆菌感染的Mo/M。这些研究将为细胞因子调控提供新的见解， 组织胞浆菌感染Mo/M.