Single-cell and spatial profiling highlights TB-induced myofibroblasts as drivers of lung pathology
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jem_20251067.pdf
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Published version
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12.37 MB
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5382a6246290662dc8c92c621803c7fb
Date Issued
March 2, 2026
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Ian M. Mbano, Nuo Liu, Marc H. Wadsworth, Mark J. Chambers, Thabo Mpotje, Osaretin E. Asowata, Sarah K. Nyquist, Kievershen Nargan, Duran Ramsuran, Farina Karim, Travis K. Hughes, Joshua D. Bromley, Robert Krause, Threnesan Naidoo, Liku B. Tezera, Michaela T. Reichmann, Sharie Keanne Ganchua, Henrik N. Kløverpris, Kaylesh J. Dullabh, Rajhmun Madansein, Sergio Triana, Adrie J.C. Steyn, Bonnie Berger, Mohlopheni J. Marakalala, Gabriele Pollara, Sarah M. Fortune, JoAnne L. Flynn, Paul T. Elkington, Alex K. Shalek, Alasdair Leslie; Single-cell and spatial profiling highlights TB-induced myofibroblasts as drivers of lung pathology. J Exp Med 2 March 2026; 223 (3): e20251067.
Version
Final published version
Abstract
Tuberculosis (TB) typically causes lung destruction and fibrosis, leading to ∼1.3 million deaths annually. The cellular drivers of human TB immunopathology remain poorly defined. We performed single-cell RNA sequencing and spatial transcriptomics on lung tissues from TB-infected and TB-negative individuals, identifying 30 distinct immune, parenchymal, and stromal cell subsets. Several were linked to TB pathology and corroborated through immunohistochemistry, flow cytometry, and independent human datasets. Fibroblasts were identified as major drivers in both active TB granuloma and TB-diseased lung tissue. In particular, the MMP1+CXCL5+ fibroblast subset, expressing a myofibroblast-like gene signature, was associated with severe disease and higher bacterial burden in nonhuman primate granulomas. Network analyses revealed cross talk between MMP1+CXCL5+ fibroblasts and SPP1+ macrophages within the granuloma cuff, which has been reported in other disease contexts, and may play an important role in TB immunopathology. Our findings highlight previously unappreciated cell populations and potential targets for novel TB therapies.
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DOI of Published Version
https://doi.org/10.1084/jem.20251067
