# Single-cell and spatial profiling highlights TB-induced myofibroblasts as drivers of lung pathology

## TL;DR

This study uses single-cell and spatial profiling to identify specific fibroblasts and macrophages linked to TB lung damage, offering new therapeutic targets.

## Contribution

The study identifies MMP1+CXCL5+ fibroblasts and SPP1+ macrophages as key drivers of TB immunopathology in human lung tissues.

## Key findings

- MMP1+CXCL5+ fibroblasts are associated with severe TB disease and higher bacterial burden.
- SPP1+ macrophages interact with fibroblasts in granulomas, contributing to TB immunopathology.
- Fibroblasts are major drivers of lung pathology in both active TB granulomas and diseased lung tissue.

## Abstract

Single-cell and spatial transcriptomics of human TB lung tissues from individuals in South Africa revealed that MMP1+CXCL5+ fibroblasts and SPP1+ macrophages are linked to TB disease and TB lung granuloma, uncovering targetable cellular cross talk underlying TB immunopathology and potential avenues for host-directed therapies.

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.