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

项目摘要/摘要 在免疫学上，肉芽肿的谜团最好地反映在无菌、控制细菌和 进行性肉芽肿可以在同一肺中共存，进行性肉芽肿最终杀死宿主。这 观察结果与现代“伴随免疫：自相矛盾的免疫状态”的概念相一致。 对再次感染的抵抗力与原始感染的持久性不谋而合。在这里，我们将测试 伴随免疫发展调节巨噬细胞分化的假说，影响 肉芽肿的形成以及免疫反应和病原体之间斗争的最终结果 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地图 人结核肉芽肿中细胞群和抗菌介体的坐标。我们建议 目的如下：1)阐明人类肺结核的细胞和分子结构 肉芽肿，2)研究巨噬细胞亚群在抗菌反应中的作用 与结核肉芽肿发病机制的关系；以及3)研究T细胞亚群在促进结核病的发生中的作用。 结核肉芽肿的伴发免疫功能。我们将确定对宿主有贡献的特定细胞亚群 通过比较具有不同细菌负荷的单个结核肉芽肿和具有不同致病机制的结核肉芽肿进行防御 观察随着原发病变的进展动态变化，到早期的支气管病变 梗阻，到原发后肉芽肿。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，特别是我们发现的泡沫巨噬细胞表达TREM2。我们会 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，因此可作为生物标记物。这些研究将把加州大学洛杉矶分校的合作者聚集在一起， 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 分子生物学对伴随免疫影响机制的新认识 肉芽肿结构，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.