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

项目总结/摘要 从免疫学上讲，肉芽肿之谜最好地反映在无菌，控制杆菌， 进行性肉芽肿可在同一肺中共存，进行性肉芽肿最终杀死宿主。这 观察结果与现代概念“伴随免疫： 对再感染的抵抗力与最初感染的持续性一致”。在这里，我们将测试 假设伴随免疫的发展调节巨噬细胞分化，影响 肉芽肿的形成和最终的结果之间的战斗免疫反应和病原体 结核分枝杆菌。为此，我们将使用单细胞RNA测序和空间测序来绘制 人结核肉芽肿中细胞群和抗菌介质的坐标。我们建议 以下具体目标：1）阐明人肺结核的细胞和分子结构 肉芽肿，2）研究有助于抗菌反应的巨噬细胞亚群的作用 vs. TB肉芽肿的发病机制;和3）研究T细胞亚群在促成TB肉芽肿中的作用。 结核肉芽肿的伴随免疫。我们将确定特定的细胞亚群，有助于宿主 通过比较具有不同细菌载量的单个TB肉芽肿和具有致病性的TB肉芽肿， 检查随着原发性病变进展的动态变化， 阻塞，原发后肉芽肿。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，特别是我们发现的表达TREM 2的泡沫巨噬细胞。我们将 研究哪些T细胞群是对化疗有反应的个体的预测因子， 它们具有抗药性，因此可以作为生物标记物。这些研究将汇集加州大学洛杉矶分校的合作者， Ragon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，以获得新的洞察机制，伴随免疫影响 肉芽肿结构，以优化宿主对结核病的防御。

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.