Immunopathogenesis of Histoplasmosis and TNF

组织胞浆菌病和 TNF 的免疫发病机制

基本信息

批准号：
10377422
负责人：
GEORGE S. DEEPE
金额：
$ 21万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377422
关键词：
Anti-Infective Agents Anti-Inflammatory Agents Antifungal Agents Automobile Driving Biological Biological Process Biology CD3 Antigens CD4 Positive T Lymphocytes CTLA4 gene Cell physiology Cells Cellular Immunity Code Defect Dendritic Cells Development Disease Disinhibition Elements FOXP3 gene Family Generations Genes Genetic Glycolysis Granulocyte-Macrophage Colony-Stimulating Factor Growth Histoplasma capsulatum Histoplasmosis Host Defense Host resistance Human IL2RA gene Immune system Immunity Immunosuppressive Agents Impairment Individual Infection Infection Control Inflammation Inflammatory Interferons Interleukin-10 Investigation Life Light Link Lung Lymphocyte Subset Metabolic Metabolism Mitochondria Molecular Morbidity - disease rate Mus Mycobacterium tuberculosis Mycoses Natural Immunity Nature Paralysed Parasites Patient Care Patients Phagocytes Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiological Processes Population Preventive therapy Progressive Disease Property Regulatory Element Regulatory T-Lymphocyte Respiration Risk Shapes Signal Transduction Suppressor-Effector T-Lymphocytes Surface T-Lymphocyte T-Lymphocyte Subsets TNF gene TNFRSF1A gene Tumor Cell Necrosis Up-Regulation Ursidae Family Work Yeasts adaptive immunity antagonist cell type combat cytokine experimental study fighting frontier fungus immune function immunoregulation immunosuppressed improved in vivo insight latent infection macrophage metabolic abnormality assessment mortality mouse model pathogenic fungus programmed cell death protein 1 pulmonary function receptor receptor expression respiratory transcriptome transcriptome sequencing transcriptomics

Anti-Infective Agents Anti-Inflammatory Agents Antifungal Agents Automobile Driving Biological Biological Process Biology CD3 Antigens CD4 Positive T Lymphocytes CTLA4 gene Cell physiology Cells Cellular Immunity Code Defect Dendritic Cells Development Disease Disinhibition Elements FOXP3 gene Family Generations Genes Genetic Glycolysis Granulocyte-Macrophage Colony-Stimulating Factor Growth Histoplasma capsulatum Histoplasmosis Host Defense Host resistance Human IL2RA gene Immune system Immunity Immunosuppressive Agents Impairment Individual Infection Infection Control Inflammation Inflammatory Interferons Interleukin-10 Investigation Life Light Link Lung Lymphocyte Subset Metabolic Metabolism Mitochondria Molecular Morbidity - disease rate Mus Mycobacterium tuberculosis Mycoses Natural Immunity Nature Paralysed Parasites Patient Care Patients Phagocytes Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiological Processes Population Preventive therapy Progressive Disease Property Regulatory Element Regulatory T-Lymphocyte Respiration Risk Shapes Signal Transduction Suppressor-Effector T-Lymphocytes Surface T-Lymphocyte T-Lymphocyte Subsets TNF gene TNFRSF1A gene Tumor Cell Necrosis Up-Regulation Ursidae Family Work Yeasts adaptive immunity antagonist cell type combat cytokine experimental study fighting frontier fungus immune function immunoregulation immunosuppressed improved in vivo insight latent infection macrophage metabolic abnormality assessment mortality mouse model pathogenic fungus programmed cell death protein 1 pulmonary function receptor receptor expression respiratory transcriptome transcriptome sequencing transcriptomics

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项目摘要

Project Description The pathogenic fungus, Histoplasma capsulatum, is endemic to the Midwestern and Southeastern US and is the most frequent cause of respiratory fungal infection. Activation of T cell-mediated immunity is considered to be a major mechanism for host control of infection. Although most infections are mild, in immunosuppressed individuals it may become life-threatening. The tumor necrosis factor (TNF)- antagonists are one of the more common immunosuppressive drugs that undermine immunity and predispose to progressive histoplasmosis. These agents have improved the lives of many with inflammatory diseases yet put them at risk for disseminat- ed histoplasmosis. As in humans, neutralization of TNF- in mice disables immunity to the fungus. In infected mice given anti-TNF-we discovered that conventional lung Foxp3-CD4+ T cells inhibited the ability of IFN-- stimulated M to kill yeast cells. Within this population, we identified the presence of a Foxp3-CD4+CD25- T cell subset that bears multiple inhibitory receptors including but not limited to PD-1, Tim-3, and TIGIT. We postulate this T cell subpopulation disarms the growth inhibitory properties of activated macrophages and dendritic cells. In the first aim we will 1) determine if this subset directly impairs the ability of M stimulated with IFN- or GM- CSF or dendritic cells to eliminate the fungus; 2) determine if signaling through TNF receptor 1 or 2 is key for the emergence of this population, and 3) ascertain if these cells negatively regulate immunity in vivo. In the second aim, we will examine the transcriptome of these cells to identify regulatory elements that prompt the increased expression of inhibitory receptors. In parallel, we will examine the metabolic properties of these cells to determine if changes in metabolism may account for the upregulation in inhibitory receptors. We will unite metabolism with RNA-seq to identify interconnecting networks between metabolism and transcriptomics These studies will provide new insights into the biology of T cells in the context of TNF- antagonism.

项目描述致病的真菌，组织囊肿，是中西部和东南部的内在，是最常见的呼吸真菌感染原因。 T细胞介导的免疫的激活被认为是成为感染宿主控制的主要机制。尽管大多数感染是温和的，但在免疫抑制个人可能会威胁生命。肿瘤坏死因子（TNF） - 拮抗剂是更多的拮抗剂之一普通的免疫抑制药物，破坏了对进行性组织性肿瘤的免疫组织化学和易感性。这些药物通过炎症性疾病改善了许多人的生活 ED组织质症。就像在人类中一样，小鼠中TNF-的中和化障碍对真菌的免疫力。在感染中给予抗TNF-的小鼠我们发现常规的肺Foxp3-CD4+ T细胞抑制了IFN---- 刺激的M杀死酵母细胞。在该人群中，我们确定了FOXP3-CD4+CD25- T细胞的存在带有多个抑制受体的子集，包括但不限于PD-1，TIM-3和Tigit。我们假设该T细胞亚群解除活化巨噬细胞和树突状细胞的生长抑制特性。在第一个目的中，我们将1）确定该子集是否直接损害了IFN-或GM-刺激的M的能力。 CSF或树突状细胞以消除真菌； 2）确定通过TNF受体1或2发出信号是否是关键该人群的出现，以及3）确定这些细胞是否在体内负调节免疫力。在第二个目的，我们将检查这些细胞的转录组，以确定促使的调节元素抑制受体的表达增加。同时，我们将检查这些细胞的代谢特性确定新陈代谢的变化是否可能解释抑制受体的上调。我们将团结起来用RNA-Seq的代谢来识别代谢和转录组学之间的互连网络这些在TNF-拮抗的背景下，研究将为T细胞的生物学提供新的见解。