Single-cell and spatial profiling reveals a role for tuberculosis-induced myofibroblasts in lung immunopathology

Abstract

Tuberculosis (TB) remains a global health challenge, causing ~1.3 million deaths annually. Pulmonary TB
47 often leads to lung destruction and fibrosis, yet the cellular drivers of human TB immunopathology remain
48 poorly defined due to limited access to relevant tissues and differences from animal models. We performed
49 single-cell RNA-sequencing and spatial transcriptomics on lung tissues from TB-infected and TB-negative
50 individuals in a highly endemic South African region. We identified 30 distinct immune, parenchymal, and
51 stromal cell subsets, with several linked to TB pathology and corroborated through immunohistochemistry,
52 flow cytometry, and an independent human lymph node granuloma cohort. Among these, we found that 53 fibroblasts were a major driver of intercellular interaction in both active TB granuloma and TB-diseased lung 54 tissue. In particular, the MMP1⁺CXCL5⁺ fibroblast subset, which expressed elevated levels of a myofibroblast55 like gene signature, was associated with severe disease, as well as higher bacterial burden in non-human 56 primate granulomas. Network analyses revealed crosstalk between MMP1⁺CXCL5⁺ fibroblasts and SPP1⁺ 57 macrophages within the granuloma cuff, which has been reported in other disease contexts, and may play an 58 important role in the immunopathology of TB. Overall, our findings highlight previously unappreciated cell 59 populations and interactions that may be targetable in host-directed TB therapies.

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Identifiers

ORCID for Liku Tezera: orcid.org/0000-0002-7898-6709

ORCID for Michaela T Reichmann: orcid.org/0000-0002-3015-9827

ORCID for Paul Elkington: orcid.org/0000-0003-0390-0613

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