Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control,Immunity

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Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control
Immunity ( IF 25.5 ) Pub Date : 2022-04-27 , DOI: 10.1016/j.immuni.2022.04.004
Hannah P Gideon ₁ , Travis K Hughes ₂ , Constantine N Tzouanas ₂ , Marc H Wadsworth ₃ , Ang Andy Tu ₄ , Todd M Gierahn ₄ , Joshua M Peters ₅ , Forrest F Hopkins ₆ , Jun-Rong Wei ₆ , Conner Kummerlowe ₇ , Nicole L Grant ₈ , Kievershen Nargan ₉ , Jia Yao Phuah ₈ , H Jacob Borish ₈ , Pauline Maiello ₈ , Alexander G White ₈ , Caylin G Winchell ₁₀ , Sarah K Nyquist ₁₁ , Sharie Keanne C Ganchua ₈ , Amy Myers ₈ , Kush V Patel ₈ , Cassaundra L Ameel ₈ , Catherine T Cochran ₈ , Samira Ibrahim ₂ , Jaime A Tomko ₈ , Lonnie James Frye ₈ , Jacob M Rosenberg ₁₂ , Angela Shih ₁₃ , Michael Chao ₆ , Edwin Klein ₁₄ , Charles A Scanga ₁ , Jose Ordovas-Montanes ₁₅ , Bonnie Berger ₁₆ , Joshua T Mattila ₁₇ , Rajhmun Madansein ₁₈ , J Christopher Love ₁₉ , Philana Ling Lin ₂₀ , Alasdair Leslie ₂₁ , Samuel M Behar ₂₂ , Bryan Bryson ₅ , JoAnne L Flynn ₁ , Sarah M Fortune ₂₃ , Alex K Shalek ₂₄

Affiliation

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.
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; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Africa Health Research Institute, Durban, South Africa.
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; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 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; Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh PA, USA.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Cardiothoracic Surgery, University of KwaZulu Natal, Durban, South Africa.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Africa Health Research Institute, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; Department of Infection and Immunity, University College London, London, UK.
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, 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; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

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.

中文翻译：

猕猴肺肉芽肿的多模式分析揭示了结核病控制的细胞相关性

结核分枝杆菌肺部感染导致复杂的多细胞结构：肉芽肿。在一些肉芽肿中，免疫活动促进细菌清除，但在其他肉芽肿中，细菌持续存在并生长。我们通过共同注册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 测序和细菌清除措施，确定了食蟹猴肺部肉芽肿中细菌控制的相关性。细菌持续存在于富含肥大细胞、内皮细胞、成纤维细胞和浆细胞的肉芽肿中，通过 2 型免疫和伤口愈合途径在它们之间发出信号。驱动细菌控制的肉芽肿的特点是细胞生态系统富含 1 型、17 型、干细胞样和细胞毒性 T 细胞，参与涉及不同细胞群的促炎信号网络。感染后期出现的肉芽肿显示出限制性肉芽肿的功能特征，并且更有能力杀死 Mtb。我们的结果定义了肉芽肿消退（缺乏）的复杂多细胞生态系统，并突出了可用于开发新的结核病疫苗和治疗策略的宿主免疫靶标。

更新日期：2022-04-27

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