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

作者：Hannah Priyadarshini Gideon, Travis K. Hughes, Constantine N. Tzouanas, Marc H. Wadsworth, Ang Andy Tu, Todd M. Gierahn, Joshua M. Peters, Forrest F. Hopkins, Jun-Rong Wei, Conner Kummerlowe, Nicole L. Grant, Kievershen Nargan, Jia Yao Phuah, Henry Jacob Borish, Pauline A Maiello, Alexander G. White, Caylin G. Winchell, Sarah Kate Nyquist, Sharie Keanne C. Ganchua, Amy J. Myers, Kush V. Patel, Cassaundra L. Ameel, Catherine T. Cochran, Samira Ibrahim, Jaime A. Tomko, Lonnie James Frye, Jacob M. Rosenberg, Angela R. Shih, Michael C. Chao, Edwin C. Klein, Charles A. Scanga, José Ordovás-Montañés, Bonnie Berger, Joshua T. Mattila, Rajhmun Madansein, John Christopher Love, Philana Ling Lin, Alasdair J. Leslie, Samuel M. Behar, Bryan D. Bryson, JoAnne L. Flynn, Sarah M. Fortune, Alex K. Shalek · 发表于：Immunity · 年份：2022 · DOI：10.1016/j.immuni.2022.04.004 · 被引用次数：300 · 研究领域：Tuberculosis Research and Epidemiology、Mycobacterium research and diagnosis、Single-cell and spatial transcriptomics

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.