Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA.
Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Immunity. 2022 May 10;55(5):827-846.e10. doi: 10.1016/j.immuni.2022.04.004. Epub 2022 Apr 27.
Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing, and measures of bacterial clearance. Bacterial persistence occurred in granulomas enriched for mast, endothelial, fibroblast, and plasma cells, signaling amongst themselves via type 2 immunity and wound-healing pathways. Granulomas that drove bacterial control were characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks involving diverse cell populations. Granulomas that arose later in infection displayed functional characteristics of restrictive granulomas and were more capable of killing Mtb. Our results define the complex multicellular ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB.
肉芽肿。在一些肉芽肿中，免疫活动促进了细菌的清除，但在另一些肉芽肿中，细菌则持续存在并生长。我们通过将纵向正电子发射断层扫描和计算机断层扫描成像、单细胞 RNA 测序以及细菌清除的测量结果进行配准，鉴定了食蟹猴肺部肉芽肿中与细菌控制相关的指标。富含肥大细胞、内皮细胞、成纤维细胞和浆细胞的肉芽肿中存在细菌持续存在的情况，它们通过 2 型免疫和伤口愈合途径相互传递信号。而那些驱动细菌控制的肉芽肿则以富含 1 型-17 型、干细胞样和细胞毒性 T 细胞的细胞生态系统为特征，这些细胞参与涉及多种细胞群体的促炎信号网络。在感染后期出现的肉芽肿表现出限制型肉芽肿的功能特征，并且更有能力杀死 Mtb。我们的研究结果定义了（缺乏）肉芽肿消退的复杂多细胞生态系统，并强调了宿主免疫靶点，这些靶点可以被利用来开发新的结核病疫苗和治疗策略。
