Immunopathogenesis of Histoplasmosis and TNF

组织胞浆菌病和 TNF 的免疫发病机制

• 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
• 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

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， 呼吸道真菌感染的最常见原因。 T 细胞介导的免疫的激活被认为 是宿主控制感染的主要机制。尽管大多数感染都是轻微的，但在免疫抑制的情况下 个人可能会危及生命。肿瘤坏死因子 (TNF)-α 拮抗剂是目前最有效的拮抗剂之一。 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。 ed 组织胞浆菌病。与人类一样，小鼠体内 TNF-α 的中和会导致对真菌的免疫力丧失。在被感染的 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M杀死酵母细胞。在这个群体中，我们发现存在 Foxp3-CD4+CD25- T 细胞 具有多种抑制性受体的子集，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- 或 GM- 刺激的 M 的能力 脑脊液或树突状细胞消灭真菌； 2) 确定通过 TNF 受体 1 或 2 的信号传导是否是关键 该群体的出现，3) 确定这些细胞是否对体内免疫产生负调节。在 第二个目标，我们将检查这些细胞的转录组，以确定促进 抑制性受体表达增加。同时，我们将检查这些细胞的代谢特性 以确定代谢的变化是否可以解释抑制性受体的上调。我们将团结起来 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。