HIF Regulation of Histoplasma Pathogenesis

HIF 对组织胞浆菌发病机制的调节

基本信息

批准号：
10084261
负责人：
GEORGE S. DEEPE
金额：
$ 40.13万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084261
关键词：
Affect Animals Antifungal Agents Area Autophagocytosis Behavior Biological Biology CD11 Antigens Cell Hypoxia Cell physiology Cells Cellular Metabolic Process Central America Chemicals Data Defect Effector Cell Elements Environment Gene Activation Generations Genetic Transcription Glycine Granulocyte-Macrophage Colony-Stimulating Factor Granuloma Growth Histoplasma Histoplasma capsulatum Histoplasmosis Host Defense Host resistance Human Hypoxia ITGB2 gene Immune Immune response Immunity Immunosuppression Impairment Infection Infection Control Inflammatory Ingestion Innate Immune Response Interferons Interleukin-10 Interleukins Licensing Malignant Neoplasms Mediating Metabolic Metabolism MicroRNAs Mus Mutant Strains Mice Myeloid Cells Natural Immunity Nodal Outcome Pathogenesis Pathology Phagocytes Pharmacology Physiological Positioning Attribute Pre-Clinical Model Predisposition Procollagen-Proline Dioxygenase Production Property Publications Regulation Reporting Respiratory Tract Infections Role Sentinel Signal Transduction Soil South America T-Cell Development TNF gene Testing Therapeutic Work Yeasts adaptive immunity antimicrobial arm chemokine cytokine dectin 1 fungus in vivo inhibitor/antagonist insight macrophage metabolic fitness metabolic phenotype microbial monocyte pathogen pathogenic fungus response transcription factor translational impact

项目摘要

Project Summary The dimorphic fungus, Histoplasma capsulatum (Hc), is endemic to the Midwestern and Southeastern US and is the most frequent cause of fungal respiratory infection. Yeast cells thrive in the intracellular environment of macrophages (M) until these phagocytes are activated by cytokines such as interferon- or granulocyte M colony-stimulating factor. The transcriptional elements that license M to promote clearance of the fungus are largely unknown. We have discovered that the transcription factors hypoxia inducing factors (HIF)-1 and -2 calibrate the behavior of M infected with Hc. In a recent publication, we reported that the lack of HIF-1 in M exacerbates infection with Hc by promoting the generation of interleukin (IL)-10. The absence of both HIF-1 and -2 further exaggerates IL-10 production by M. Excessive IL-10 dampens the ability of activating cytokines to arm the anti-Hc function of M. We demonstrate that Hc induces HIFs and that pharmacologically inflating HIF accrual enhances the anti-Hc activity of mouse and human M. These data triggered two hypotheses: 1) HIFs in M are required to temper IL-10 generation, and 2) pharmacologically amplifying expression of HIFs arms M to exert anti-Hc activity. To test these hypotheses, we propose three Specific Aims. Aim 1 will examine the interplay between HIFs and metabolism. Specifically, we will determine if a glycolytic metabolite initiates and tumor necrosis factor- sustains expression of HIFs. We will determine if overproduction of a specific metabolite by infected HIF-deficient cells promotes IL-10 release. Specific Aim 2 will examine how HIFs regulate IL-10. We will determine if miRNA-27a is involved in the generation of IL-10 and if IL-10 modifies the metabolism of HIF- deficient cells. We will test the possibility that a metabolic product regulates the expression of an miRNA that controls the decay of IL-10 transcription. We will ascertain if IL-1receptor antagonist is a downstream effector of IL-10-mediated inhibition of M function. Specific Aim 3 will investigate how pharmacological activation of HIFs promotes the anti-Hc activity of MWe will identify a mechanism and the in vivo effect of these agents. We expect these studies to provide a greater understanding of the regulation of M function in response to Hc.

项目概要二形性真菌荚膜组织胞浆菌 (Hc) 是美国中西部和东南部的特有种它是真菌呼吸道感染的最常见原因。酵母细胞在细胞内环境中茁壮成长。巨噬细胞 (M) 直至这些吞噬细胞被细胞因子（如干扰素- 或粒细胞 M）激活允许 Mf 促进真菌清除的转录元件是我们发现转录因子缺氧诱导因子（HIF）-1α和-2α。校准感染 Hc 的 M 的行为在最近的一篇出版物中，我们报道了 M 中缺乏 HIF-1。 HIF-1α 的缺失会促进白细胞介素 (IL)-10 的产生，从而加重 Hc 感染。 -2 进一步夸大 M 产生的 IL-10，过多的 IL-10 会抑制激活细胞因子的能力。我们证明 Hc 会诱导 HIF，并在药理学上使 HIF 膨胀。 accrual 增强了小鼠和人类 Mf 的抗 Hc 活性。这些数据引发了两个假设：1) HIF。 M 中需要调节 IL-10 的生成，并且 2) 药理学上放大 HIF 臂 M 的表达为了检验这些假设，我们提出了三个具体目标 1 将检验。具体来说，我们将确定糖酵解代谢物是否启动和代谢。肿瘤坏死因子-α 维持 HIF 的表达我们将确定特定代谢物是否过量产生。受感染的 HIF 缺陷细胞促进 IL-10 释放具体目标 2 将研究 HIF 如何调节 IL-10。将确定 miRNA-27a 是否参与 IL-10 的生成以及 IL-10 是否改变 HIF-的代谢我们将测试代谢产物调节 miRNA 表达的可能性。我们将确定 IL-1 受体拮抗剂是否是下游效应子。 IL-10 介导的 Mf 功能抑制。具体目标 3 将研究 HIF 的药理学激活方式。促进 M 的抗 Hc 活性我们将确定这些药物的机制和体内效果。期望这些研究能够更好地理解 Mf 功能对 Hc 的调节。