HIF Regulation of Histoplasma Pathogenesis

HIF 对组织胞浆菌发病机制的调节

• 批准号: 10327291
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327291
• 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; antagonist; antimicrobial; arm; chemokine; cytokine; dectin 1; fungus; in vivo; inhibitor; insight; macrophage; metabolic fitness; metabolic phenotype; microbial; monocyte; pathogen; pathogenic fungus; response; transcription factor; translational impact

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.

项目摘要 这种二相性真菌，组织胞浆菌(HC)，是美国中西部和东南部特有的 是引起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)，直到这些吞噬细胞被干扰素-或粒细胞M等细胞因子激活 集落刺激因子。允许M促进真菌清除的转录元件是 很大程度上是未知的。我们发现转录因子缺氧诱导因子-1和-2 校正感染了HC的M-的行为。在最近的一篇文章中，我们报道了M-中缺乏HIF-1 通过促进白介素10的产生而加重丙型肝炎病毒的感染。缺氧诱导因子-1的缺失 -2进一步夸大了M-产生IL-10的能力。过多的IL-10抑制激活细胞因子的能力 武装M-的抗HC功能。我们证明了HC诱导了HIF，并且从药理上使HIF膨胀 可增强小鼠和人M-的抗HC活性。这些数据引发了两个假设：1)高强度聚焦 在M中需要抑制IL-10的产生，以及2)药物上放大HIF ARM M的表达 发挥抗HC活性。为了检验这些假设，我们提出了三个具体目标。目标1将研究 HIF与新陈代谢之间的相互作用。具体地说，我们将确定糖酵解代谢物是否启动并 肿瘤坏死因子-支持HIFs的表达。我们将确定一种特定代谢物的过量生产 通过感染HIF缺陷细胞促进IL-10的释放。《特定目标2》将研究HIF如何调节IL-10。我们 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- 缺乏细胞。我们将测试代谢产物调节miRNA表达的可能性 控制IL-10转录的衰退。我们将确定IL-1受体拮抗剂是否是 IL-10介导的M-功能抑制。具体目标3将调查HIF的药理激活如何 促进M-的抗HC活性我们将确定这些药物的作用机制和体内效应。我们 希望这些研究能更好地理解HC对M-功能的调节作用。

项目成果

Crosstalk Between Autophagy and Hypoxia-Inducible Factor-1α in Antifungal Immunity.

• DOI: 10.3390/cells9102150
• 发表时间: 2020-09-23
• 期刊: Cells
• 影响因子: 6
• 作者: Quäschling T;Friedrich D;Deepe GS Jr;Rupp J
• 通讯作者: Rupp J

Restraint of Fumarate Accrual by HIF-1α Preserves miR-27a-Mediated Limitation of Interleukin 10 during Infection of Macrophages by Histoplasma capsulatum.

• DOI: 10.1128/mbio.02710-21
• 发表时间: 2021-12-21
• 期刊: mBio
• 影响因子: 6.4
• 作者: Evans HM;Schultz DF;Boiman AJ;McKell MC;Qualls JE;Deepe GS Jr
• 通讯作者: Deepe GS Jr

Notch regulates Histoplasma capsulatum clearance in mouse lungs during innate and adaptive immune response phases in primary infection.

• DOI: 10.1002/jlb.4a1221-743r
• 发表时间: 2022-11
• 期刊: JOURNAL OF LEUKOCYTE BIOLOGY
• 影响因子: 5.5
• 作者: Huang, Shuo;Deepe, George S., Jr.
• 通讯作者: Deepe, George S., Jr.

Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials.

• DOI: 10.1128/mbio.00023-21
• 发表时间: 2021-03-30
• 期刊: mBio
• 影响因子: 6.4
• 作者: Shima K;Kaufhold I;Eder T;Käding N;Schmidt N;Ogunsulire IM;Deenen R;Köhrer K;Friedrich D;Isay SE;Grebien F;Klinger M;Richer BC;Günther UL;Deepe GS Jr;Rattei T;Rupp J
• 通讯作者: Rupp J