Single-cell profiling reveals a role for tuberculosis-induced myofibroblasts in the immunopathology of infected lungs 3060

Abstract Description Tuberculosis (TB) remains a serious global health challenge, where most cases are pulmonary and frequently lead to post-tuberculosis lung disease (PTLD) with gross tissue destruction and fibrosis. However, the mechanisms of TB immunopathology are poorly understood due to challenges associated with obtaining relevant human tissues and differences from animal models. To address this, we performed single-cell RNA-sequencing on human lung tissues from 9 participants with PTLD and 4 controls from a highly TB-endemic region of South Africa, recovering 19,632 high-quality single cells. We identified several cellular subsets not previously linked to human TB, validated by functional assays and bulk RNA-seq of independent human granuloma samples. By comparing with lung stromal signatures and Human Lung Cell Atlas, as well as through unbiased gene network analyses, we identified a myofibroblast-like MMP1+CXCL5+ Fibroblast subset associated with severe disease, supported by additional primary human samples. Further analyses on a non-human primate granuloma dataset linked this subset to higher bacterial burden. Through cell network analyses, we revealed prominent crosstalk between MMP1+CXCL5+ Fibroblasts and macrophages that suggested a previously underappreciated role for SPP1+ Macrophages in TB-diseased lung tissues. Overall, our study identifies important cell populations that may be exploitable as novel targets in host-directed therapies for TB. Funding Sources Wellcome Trust grant 210662/Z/18/Z ; Bill and Melinda Gates Foundation grant OPP1137006 ;Medical Research Council (MRC) MR/W025728/1: MR CF2021-2\126; NIH contract IMPAc-TB 75N93019C00071. Topic Categories Computational and Systems Immunology (COMP)

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Publication Details

Journal
The Journal of Immunology
Published
2025-11-01
DOI
https://doi.org/10.1093/jimmun/vkaf283.900
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
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article

Single-cell profiling reveals a role for tuberculosis-induced myofibroblasts in the immunopathology of infected lungs 3060

Mark A. Chambers, Sergio Triana, Ian Mbano, Mohlopheni J. Marakalala et al.
The Journal of Immunology
Single-cell and spatial transcriptomics
article

Single-cell profiling reveals a role for tuberculosis-induced myofibroblasts in the immunopathology of infected lungs 3060

Mark A. Chambers, Sergio Triana, Ian Mbano, Mohlopheni J. Marakalala, Osaretin E. Asowata, Liku B. Tezera, Sarah K. Nyquist, Bonnie Berger, Michaela Reichmann, Travis K. Hughes, Joshua D. Bromley, Thabo Mpotje, Rajhmun Madansein, Farina Karim, Robert G. E. Krause, Alasdair J. Leslie, Adrie J. C. Steyn, Kaylesh J Dullabh, JoAnne L. Flynn, Duran Ramsuran, Paul T. Elkington, Alex K. Shalek, Sarah M. Fortune, Kievershen Nargan, Henrik N. Kløverpris, Nuo Liu, Marc Wardsworth, C Ganchua, Sharie Keanne
article en

Abstract

Abstract Description Tuberculosis (TB) remains a serious global health challenge, where most cases are pulmonary and frequently lead to post-tuberculosis lung disease (PTLD) with gross tissue destruction and fibrosis. However, the mechanisms of TB immunopathology are poorly understood due to challenges associated with obtaining relevant human tissues and differences from animal models. To address this, we performed single-cell RNA-sequencing on human lung tissues from 9 participants with PTLD and 4 controls from a highly TB-endemic region of South Africa, recovering 19,632 high-quality single cells. We identified several cellular subsets not previously linked to human TB, validated by functional assays and bulk RNA-seq of independent human granuloma samples. By comparing with lung stromal signatures and Human Lung Cell Atlas, as well as through unbiased gene network analyses, we identified a myofibroblast-like MMP1+CXCL5+ Fibroblast subset associated with severe disease, supported by additional primary human samples. Further analyses on a non-human primate granuloma dataset linked this subset to higher bacterial burden. Through cell network analyses, we revealed prominent crosstalk between MMP1+CXCL5+ Fibroblasts and macrophages that suggested a previously underappreciated role for SPP1+ Macrophages in TB-diseased lung tissues. Overall, our study identifies important cell populations that may be exploitable as novel targets in host-directed therapies for TB. Funding Sources Wellcome Trust grant 210662/Z/18/Z ; Bill and Melinda Gates Foundation grant OPP1137006 ;Medical Research Council (MRC) MR/W025728/1: MR CF2021-2\126; NIH contract IMPAc-TB 75N93019C00071. Topic Categories Computational and Systems Immunology (COMP)

The Journal of ImmunologyVol. 214(Supplement_1)
University of Pittsburgh (US), Ragon Institute of MGH, MIT and Harvard (US), Africa Health Research Institute (ZA), University of Southampton (GB), University College London (GB), Massachusetts Institute of Technology (US), University of KwaZulu-Natal (ZA)
Openalex Percentile: Top 68%
Single-cell and spatial transcriptomics
DOIOpen Access PDFOpenAlex
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