Dynamics of the cellular and molecular architecture of human pulmonary TB granulomas

人肺结核肉芽肿细胞和分子结构的动力学

基本信息

批准号：
10569668
负责人：
ROBERT L MODLIN
金额：
$ 64.78万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-10 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569668
关键词：
Acute Address Affect Animals Anti-Inflammatory Agents Architecture Area Atherosclerosis Bacillus Bacteria Biological Markers Cells Chronic Clinical Collection Communicable Diseases Complex Confusion Data Development Disease Evolution Foamy Macrophage Genes Granuloma Granulomatous Host Defense Human Immune response Immunity Immunologics Immunology Individual Infection Infection Control Infectious granuloma Inflammation Inflammatory Inflammatory Response Invaded Learning Leprosy Lesion Lung Lymphocyte Macrophage Macrophage Activation Maps Mediating Mediator Mining Modeling Modernization Molecular Molecular Biology Molecular Profiling Mycobacterium tuberculosis Mycoses Nature Obstruction Outcome Parasitic infection Pathogenesis Pathway interactions Patients Population Prevention strategy Primary Infection Primary Lesion Public Health Pulmonary Tuberculosis Reaction Resistance Role Sterility Structure T cell response T-Lymphocyte TREM2 gene Testing Tuberculosis antimicrobial antimicrobial peptide cell type chemotherapy healing immunological status insight interest lipid metabolism microbicide monocyte nonhuman primate pathogen pathogenic microbe programs response single-cell RNA sequencing success treatment response tuberculosis granuloma tuberculosis immunity

项目摘要

PROJECT SUMMARY/ABSTRACT Immunologically, the enigma of the granuloma is best reflected in that sterile, bacillus-controlling, and progressive granulomas can coexist in the same lung, with the progressive form ultimately killing the host. This observation is consistent with the modern concept of “concomitant immunity: the paradoxical immune status in which resistance to reinfection coincides with the persistence of the original infection”. Here, we will test the hypothesis that the development of concomitant immunity regulates macrophage differentiation, influencing granuloma formation and ultimately the outcome of the battle between the immune response and the pathogen Mycobacterium tuberculosis. To do so, we will use single cell RNA sequencing and spatial sequencing to map the coordinates of cell populations and antimicrobial mediators in human TB granulomas. We propose the following specific aims: 1) elucidate the cellular and molecular architecture of human pulmonary TB granulomas, 2) investigate the role of macrophage subpopulations that contribute to the antimicrobial response vs. pathogenesis of TB granulomas; and 3) investigate the role of T cell subpopulations in contributing to concomitant immunity in TB granulomas. We will identify specific cell subpopulations that contribute to host defense by comparing individual TB granulomas with varying bacterial loads and those with pathogenesis by examining the dynamic change with the progression of primary lesions, to early lesions with bronchial obstruction, to post-primary granulomas. We will determine the role of macrophage subpopulations in host defense and pathogenesis, in particular the foamy macrophages that we discovered express TREM2. We will investigate which T cell populations are predictors of individuals that respond to chemotherapy versus those that are resistant and therefore serve as biomarkers. These studies will bring together collaborators at UCLA, the Ragon Institute and the Institut Pasteur de Tunis with expertise in clinical tuberculosis, immunology and molecular biology to gain new insight into the mechanisms by which concomitant immunity influences granuloma structure to optimize host defense against TB.

项目概要/摘要从免疫学角度来看，肉芽肿的谜团最能体现在其无菌、控制杆菌和进行性肉芽肿可以在同一肺中共存，进行性肉芽肿最终会杀死宿主。观察结果与“伴随免疫：矛盾的免疫状态”的现代概念是一致的。对再感染的抵抗力与原始感染的持续性一致”。假设伴随免疫的发展调节巨噬细胞分化，影响肉芽肿的形成以及免疫反应和病原体之间战斗的最终结果为此，我们将使用单细胞 RNA 测序和空间测序来绘制图谱。我们提出了人类结核肉芽肿中细胞群和抗菌介质的坐标。以下具体目标：1）阐明人类肺结核的细胞和分子结构肉芽肿，2) 研究巨噬细胞亚群对抗菌反应的作用与结核肉芽肿的发病机制比较；3) 研究 T 细胞亚群在促成我们将确定有助于宿主的特定细胞亚群。通过比较具有不同细菌载量的个体结核肉芽肿和具有发病机制的结核肉芽肿来防御检查原发病变进展到支气管早期病变的动态变化我们将确定巨噬细胞亚群在宿主中的作用。防御和发病机制，特别是我们发现表达 TREM2 的泡沫巨噬细胞。研究哪些 T 细胞群是对化疗有反应的个体的预测因子这些研究将汇集加州大学洛杉矶分校的合作者，拉贡研究所和突尼斯巴斯德研究所在临床结核病、免疫学和分子生物学，以获得对伴随免疫影响机制的新见解肉芽肿结构优化宿主对结核病的防御。