Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27710, USA.
Cell. 2021 Apr 1;184(7):1757-1774.e14. doi: 10.1016/j.cell.2021.02.046. Epub 2021 Mar 23.
The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition. Using the zebrafish-Mycobacterium marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacterium tuberculosis-infected macaques reveal that, even in the presence of robust type 1 immune responses, countervailing type 2 signals associate with macrophage epithelialization. We find that type 2 immune signaling, mediated via stat6, is absolutely required for epithelialization and granuloma formation. In mixed chimeras, stat6 acts cell autonomously within macrophages, where it is required for epithelioid transformation and incorporation into necrotic granulomas. These findings establish the signaling pathway that produces the hallmark structure of mycobacterial infection.
结核分枝杆菌中病原体-免疫的中心界面是肉芽肿，这是一种复杂的宿主免疫结构，决定着感染轨迹和生理。肉芽肿中的巨噬细胞经历了剧烈的转变，整个上皮模块被诱导并定义了肉芽肿的结构。在结核分枝杆菌中，相对较少的是宿主信号触发这种转变。我们使用斑马鱼-海分枝杆菌模型，确定了肉芽肿巨噬细胞转化的基础。对斑马鱼肉芽肿的单细胞 RNA 测序分析和结核分枝杆菌感染猕猴的分析表明，即使存在强烈的 1 型免疫反应，拮抗的 2 型信号也与巨噬细胞上皮化相关。我们发现，2 型免疫信号通过 stat6 介导，对于上皮化和肉芽肿形成是绝对必需的。在混合嵌合体中，stat6 在巨噬细胞中自主发挥作用，在巨噬细胞中需要它来进行上皮样转化并纳入坏死性肉芽肿。这些发现确立了产生分枝杆菌感染标志性结构的信号通路。
