Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control
Gideon, Hannah P ; Hughes, Travis K ; Tzouanas, Constantine N ; Wadsworth, Marc H ; Tu, Ang Andy ; Gierahn, Todd M ; Peters, Joshua M ; Hopkins, Forrest F ; Wei, Jun-Rong ; Kummerlowe, Conner ... show 10 more
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Authors
Hughes, Travis K
Tzouanas, Constantine N
Wadsworth, Marc H
Tu, Ang Andy
Gierahn, Todd M
Peters, Joshua M
Hopkins, Forrest F
Wei, Jun-Rong
Kummerlowe, Conner
Grant, Nicole L
Nargan, Kievershen
Phuah, Jia Yao
Borish, H Jacob
Maiello, Pauline
White, Alexander G
Winchell, Caylin G
Nyquist, Sarah K
Ganchua, Sharie Keanne C
Myers, Amy
Patel, Kush V
Ameel, Cassaundra L
Cochran, Catherine T
Ibrahim, Samira
Tomko, Jaime A
Frye, Lonnie James
Rosenberg, Jacob M
Shih, Angela
Chao, Michael
Klein, Edwin
Scanga, Charles A
Ordovas-Montanes, Jose
Berger, Bonnie
Mattila, Joshua T
Madansein, Rajhmun
Love, J Christopher
Lin, Philana Ling
Leslie, Alasdair
Behar, Samuel M
Bryson, Bryan
Flynn, JoAnne L
Fortune, Sarah M
Shalek, Alex K
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UMass Chan Affiliations
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Abstract
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.
Source
Gideon HP, Hughes TK, Tzouanas CN, Wadsworth MH 2nd, Tu AA, Gierahn TM, Peters JM, Hopkins FF, Wei JR, Kummerlowe C, Grant NL, Nargan K, Phuah JY, Borish HJ, Maiello P, White AG, Winchell CG, Nyquist SK, Ganchua SKC, Myers A, Patel KV, Ameel CL, Cochran CT, Ibrahim S, Tomko JA, Frye LJ, Rosenberg JM, Shih A, Chao M, Klein E, Scanga CA, Ordovas-Montanes J, Berger B, Mattila JT, Madansein R, Love JC, Lin PL, Leslie A, Behar SM, Bryson B, Flynn JL, Fortune SM, Shalek AK. Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control. Immunity. 2022 May 10;55(5):827-846.e10. doi: 10.1016/j.immuni.2022.04.004. Epub 2022 Apr 27. PMID: 35483355; PMCID: PMC9122264.