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：
10227274
负责人：
GEORGE S. DEEPE
金额：
$ 25万
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227274
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 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

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.

项目描述致病性真菌，荚膜组织胞浆菌，是美国中西部和东南部的特有种， T 细胞介导的免疫激活被认为是呼吸道真菌感染的最常见原因。是宿主控制感染的主要机制，尽管大多数感染是轻微的，但在免疫抑制的情况下。肿瘤坏死因子 (TNF)-α 拮抗剂是其中一种可能危及生命的药物。常见的免疫抑制药物会破坏免疫力并导致进行性组织胞浆菌病。这些药物改善了许多患有炎症性疾病的人的生活，但也使他们面临传播的风险。与人类一样，小鼠体内的 TNF-α 的中和会导致感染者对真菌失去免疫力。给予抗 TNF-α 的小鼠我们发现传统的肺 Foxp3-CD4+ T 细胞抑制 IFN-α- 的能力刺激 Mf 杀死酵母细胞，在该群体中，我们发现存在 Foxp3-CD4+CD25-T 细胞。我们假设具有多种抑制性受体的子集，包括但不限于 PD-1、Tim-3 和 TIGIT。该 T 细胞亚群解除了活化巨噬细胞和树突状细胞的生长抑制特性。在第一个目标中，我们将 1) 确定该子集是否直接损害 IFN-α 或 GM- 刺激的 M 的能力 CSF 或树突状细胞消除真菌；2) 确定通过 TNF 受体 1 或 2 的信号传导是否是消除真菌的关键该群体的出现，以及3）确定这些细胞是否对体内免疫产生负调节。第二个目标，我们将检查这些细胞的转录组，以确定促进同时，我们将检查这些细胞的代谢特性。以确定新陈代谢的变化是否可以解释抑制性受体的上调。我们将联合起来。代谢与 RNA-seq 来识别代谢和转录组学之间的互连网络研究将为 TNF-α 拮抗背景下的 T 细胞生物学提供新的见解。