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: 10189487
• 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/10189487
• 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; 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.

致病的真菌，组织囊肿，是中西部和美国东南部的内部粒子。 是呼吸真菌感染的最常见原因。生物在 单核细胞（MO）和巨噬细胞（Mɸ）的细胞内环境 - 具有能力 采用多学科方法，包括金属学，免疫学， 细胞生物学和生物信息学，我们的研究已经确定了粒细胞的新功能 巨噬细胞刺激因子（GM-CSF）和白介素（IL）-4，有助于解释其它们 MO/Mɸ对真菌的生长的不同影响。 GM-CSF剥夺了锌的生物 细胞内同时增强活性氧的产生。最终结果 正在杀死酵母细胞。另一方面，IL-4通过强化促进细胞内存活 可用于组织的锌量。对于GM-CSF和IL-4的活动至关重要 金属硫酸盐（MTS），存储和捐赠锌和锌转运蛋白。它们是中央节点 介导细胞因子激活与效应子功能之间的联系。对于GM-CSF，MTS1和2是 必不可少的，而对于IL-4，是MT3。在此提案中，我们将建立在我们从事的工作的基础上 最后的融资周期并深入探索MT-Zinc轴如何调节GM-CSF的活性 以及人类和小鼠mo/mɸ的IL-4。我们收集了令人兴奋的数据，糖酵解控制 MTS1和2在感染的GM-CSF刺激的mo/mɸ中的表达。另一方面，MT3温度 在这些细胞中激活IL-4中的糖酵解反应。 AIM 1将破译糖酵解如何霉菌 MT1和2的表达和细胞内Zn2+分布到Bolster MO/Mɸ效应函数。目标2 将定义GM-CSF激活的mo/mɸ的细胞内变化，否认真菌进入 锌和MTS1和2对这些吞噬细胞施加的宿主防御的体内效应。目标3意志 阐明糖酵解和MT3在塑造IL-4的生理学上的相交 组织感染的mo/mɸ。这些研究将为细胞因子调节提供新的见解 在组织感染的mo/mɸ中，代谢和肠生物学。