Single-cell and spatial profiling highlights TB-induced myofibroblasts as drivers of lung pathology
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.
Authors
- Ian Mbano (ORCID: https://orcid.org/0000-0002-2583-4760)
- Mohlopheni J. Marakalala (ORCID: https://orcid.org/0000-0001-7476-1652)
- Marc H. Wadsworth (ORCID: https://orcid.org/0000-0001-9479-8516)
- Osaretin E. Asowata (ORCID: https://orcid.org/0000-0002-3936-4659)
- Threnesan Naidoo (ORCID: https://orcid.org/0000-0002-1864-4301)
- Liku B. Tezera (ORCID: https://orcid.org/0000-0002-7898-6709)
- Mark John. Chambers (ORCID: https://orcid.org/0000-0002-3712-2752)
- Sarah K. Nyquist (ORCID: https://orcid.org/0000-0002-9045-3665)
- Bonnie Berger (ORCID: https://orcid.org/0000-0002-2724-7228)
- Michaela Reichmann (ORCID: https://orcid.org/0000-0002-3015-9827)
- Travis K. Hughes
- Joshua D. Bromley (ORCID: https://orcid.org/0000-0001-8692-2740)
- Thabo Mpotje (ORCID: https://orcid.org/0000-0001-5462-6648)
- Rajhmun Madansein (ORCID: https://orcid.org/0000-0001-7306-1304)
- Robert G. E. Krause (ORCID: https://orcid.org/0000-0003-1558-0397)
- Alasdair J. Leslie (ORCID: https://orcid.org/0000-0003-2538-6467)
- Kaylesh J Dullabh (ORCID: https://orcid.org/0000-0002-2469-871X)
- Duran Ramsuran
- Kievershen Nargan
- Henrik N. Kløverpris (ORCID: https://orcid.org/0000-0002-2165-3313)
- Farina. Karim
- Nuo Liu
- Alex K. Shalek
- Sharie Keanne Ganchua
- JoAnne L. Flynn
- Adrie J.C. Steyn
- Sergio Triana
Institutions
- Broad Institute (US)
- University of Copenhagen (DK)
- Harvard University (US)
- University of Pittsburgh (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- University of Alabama at Birmingham (US)
- NIHR Southampton Biomedical Research Centre (GB)
- Africa Health Research Institute (ZA)
- VA Pittsburgh Healthcare System (US)
- Institute of Infection and Immunity (CA)
- University of Southampton (GB)
- University College London (GB)
- Massachusetts Institute of Technology (US)
- University of KwaZulu-Natal (ZA)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-10-21
- DOI
- https://doi.org/10.1084/jem.20251067
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bill and Melinda Gates Foundation
- Wellcome Trust
- National Institutes of Health
- Medical Research Council