Abstract

Background Tuberculous pericarditis (TP) can progress to tuberculous constrictive pericarditis (TB-CP), a life-threatening fibrotic syndrome. However, the cellular architecture and intercellular circuits that link granulomatous inflammation to pericardial fibrosis remain poorly defined. Methods We performed single-cell RNA sequencing (scRNA-seq) on 81,634 cells from surgically resected pericardium of six patients with TB-CP and three normal controls. Ligand-receptor and trajectory analyses were integrated with spatial transcriptomics, histology, immunohistochemistry, and multiplex immunofluorescence to map cell states, signalling pathways, and immune-stromal niches in situ. Findings We generated an integrated single-cell and spatial atlas of the human pericardium in TB-CP, delineating 14 major cell types and heterogeneous transcriptional programmes associated with granuloma formation, vascular remodelling, and fibrotic activation. Spatial mapping revealed MMP9 + macrophage-rich granulomatous cores surrounded by infiltrating CCL19 + fibroblasts and T cells. In parallel, S100A4 + endothelial cells displayed endothelial-to-mesenchymal transition-like programmes and trajectories converging on ACTA2 + myofibroblasts, supported by immune cell-derived TGF-β and VEGF signalling. Ligand-receptor analysis and spatial co-localisation suggested macrophages may act as hubs that couple immune activation to endothelial reprogramming, fibroblast activation, and T-cell recruitment within fibrotic lesions. Interpretation This human atlas defines the cellular landscape and key intercellular circuits underlying the immunopathogenesis of TB-CP. Our findings show that a spatially organised immune-endothelial-fibroblast network is associated with pericardial fibrosis and nominate VEGF/TGF-β pathways and associated cell states as potential biomarkers and therapeutic targets. Funding Nati