A single-cell transcriptomic atlas of the lungs of patients with pulmonary tuberculosis

Patients with a history of mycobacterium tuberculosis infection commonly acquire irreversible and often progressive pulmonary defects. Here, we sought to understand, at a high resolution, the mechanisms underlying structural changes and functional impairments in lungs following tuberculosis (TB). To this end, we generated the first single-cell transcriptomic landscape of the human lung after TB infection, and deciphered disease-associated cell type-specific molecular profiles, including hyperinflammation, cell death, fibrosis, and cellular senescence, a thus far unappreciated molecular event of TB pathology. We identified prominent loss of pulmonary endothelial cells and augmented pulmonary vascular inflammation as hallmarks of disability in the post-TB lung. Mechanistically, we found that blunted FOXO3 and overactivated Thrombin-THBD signaling exacerbate vascular inflammation and cellular senescence in pulmonary endothelial cells. Overall, our work depicts a comprehensive single-cell transcriptomic atlas of pulmonary TB and provides potential therapeutic targets to relieve the pulmonary impairment after TB.