GM-CSF Regulation of Zinc in Histoplasmosis

GM-CSF 对组织胞浆菌病中锌的调节

• 批准号: 8131283
• 负责人: GEORGE S. DEEPE
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131283
• 关键词: Abbreviations; Acetic Acids; Antifungal Agents; Binding; Binding Proteins; Bone Marrow; Cells; Colony Stimulating Factor Activation; Colony-Stimulating Factors; Colony-forming units; Communicable Diseases; Coupled; Data; Environment; Ethylenediamines; Exploratory/Developmental Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Histoplasma capsulatum; Histoplasmosis; Host resistance; Human; Immunity; Immunocompetent; Immunocompromised Host; In Vitro; Infection; Inflammatory; Interferon Type II; Interferons; Interleukin-4; Interleukins; Intravenous; Iron; Life; Liquid Chromatography; Macrophage Activation; Mass Spectrum Analysis; Mediating; Metals; Microbe; Molecular Sieve Chromatography; Monoclonal Antibodies; Mus; Mycelium; Organism; Pathway interactions; Pentetic Acid; Peritoneal; Phagocytes; Plasma; Polymerase Chain Reaction; Population; Proteins; Proteome; Recombinant Granulocyte-Macrophage Colony-Stimulating Factors; Regulation; Relative (related person); Reporting; Resolution; Respiratory Tract Infections; Rest; Role; Severities; Signal Transduction; Site; Small Interfering RNA; Southeastern United States; Starvation; T-Lymphocyte; Time; Trace metal; Weight; Withdrawal; Work; Yeasts; Zinc; Zinc deficiency; antimicrobial; chemokine; cytokine; deprivation; fungus; granulocyte; in vivo; intraperitoneal; killings; macrophage; novel; protein profiling; resistance mechanism; response; 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 forward metallomics approach, our studies indicate that activation of macrophages by granulocyte macrophage colony-stimulating factor (GM-CSF) sharply limits intracellular zinc content in response to infection with Hc. The deprivation of zinc is associated with marked increases in zinc binding species. We also have shown that interleukin-4 restores intracellular growth and concomitantly increases intracellular zinc. We therefore have gathered substantial data to indicate that limiting access to zinc is a major mechanism by which GM-CSF activation halts intracellular growth of Hc. This novel finding has led us to hypothesize that zinc limitation may be an important host resistance mechanism exerted by cytokines. Herein, we propose 3 specific aims. The first aim is to determine if GM-CSF activation of human macrophages decreases zinc content in host cells and Hc. In the second aim, we will quantify and identify the upregulated zinc binding proteins in both human and mouse macrophages and select candidates to silence by siRNA to determine their role in zinc regulation. Aim 3 will examine zinc content and zinc binding species among macrophage populations in mice in which GM-CSF is absent. This exploratory proposal builds upon a new and exciting observation regarding how cytokines may activate macrophages to express antifungal and perhaps antimicrobial activity. Our work will endeavor to establish the necessity of this trace metal in the host-microbe battle. PUBLIC HEALTH RELEVANCE: The pathogenic fungus, Histoplasma capsulatum, multiplies in macrophages until they are activated by cytokines. Killing of yeasts by stimulated macrophages is mediated by zinc starvation. We seek to determine how zinc depletion occurs so that these findings can offer new avenues for treatment of this fungus.

描述（由申请方提供）：双形真菌，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。使用正向金属组学方法，我们的研究表明，激活的巨噬细胞的粒细胞巨噬细胞集落刺激因子（GM-CSF）急剧限制细胞内锌含量在感染HC。锌的剥夺与锌结合物种的显著增加有关。我们还发现，白细胞介素-4恢复细胞内生长，并伴随着增加细胞内锌。因此，我们已经收集了大量的数据表明，限制获得锌是一个主要的机制，其中GM-CSF激活停止细胞内生长的HC。这一新的发现使我们推测锌限制可能是细胞因子产生的重要宿主抗性机制。为此，我们提出了三个具体目标。第一个目的是确定GM-CSF激活人巨噬细胞是否降低宿主细胞和Hc中的锌含量。在第二个目标中，我们将定量和鉴定人类和小鼠巨噬细胞中上调的锌结合蛋白，并选择通过siRNA沉默的候选蛋白，以确定它们在锌调节中的作用。目的3研究缺乏GM-CSF的小鼠巨噬细胞群中锌含量和锌结合物种。这个探索性的建议建立在一个新的和令人兴奋的观察细胞因子如何激活巨噬细胞表达抗真菌和抗菌活性。我们的工作将奋进建立这种微量金属在宿主微生物战斗中的必要性。 公共卫生相关性：致病真菌荚膜组织胞浆菌在巨噬细胞中繁殖，直到它们被细胞因子激活。激活的巨噬细胞对酵母的杀伤作用是由锌饥饿介导的。我们试图确定锌耗竭是如何发生的，以便这些发现可以为治疗这种真菌提供新的途径。