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

Hannah P.Gideon, Travis K.Hughes, Constantine N.Tzouanas, Marc H.WadsworthII, Ang AndyTu, Todd M.Gierahn, Joshua M.Peters, Forrest F.Hopkins, Jun-RongWei, Conner Kummerlowe, Nicole L.Grant, Kievershen Nargan, Jia YaoPhuah, H. JacobBorish, Pauline Maiello, Alexander G.White, Caylin G.Winchell, Sarah K.Nyquist, Sharie Keanne C.Ganchua, Amy Myers, Kush V.Patel, Cassaundra L.Ameel, Catherine T.Cochran, Samira Ibrahim, Jaime A.Tomko, Lonnie JamesFrye, Jacob M.Rosenberg, Angela Shih, Michael Chao, Edwin Klein, Charles A.Scanga, Jose Ordovas-Montanes, Bonnie Berger, Joshua T.Mattila, Rajhmun Madansein, J. ChristopherLove, Philana LingLin, Alasdair Leslie, Samuel M.Behar, Bryan Bryson, JoAnne L. Flynn, Sarah M. Fortune, Alex K.Shalek

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.



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Snapshot 1 (3rd Nov 2022)

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Created: 20th May 2022 at 17:42

Last updated: 4th Aug 2023 at 14:56

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