Spatial profiling reveals TREM2+ macrophages as central to Mycobacterium tuberculosis pathogenesis in human pulmonary tuberculosis

While organized granulomas have long been the focus of TB pathogenesis research, the early development of TB pneumonia has been underexplored. Using spatial transcriptomics, high-resolution proteomics, and scRNA-seq on human pulmonary TB lesions, we reveal a striking compartmentalization of immune responses between early pneumonia and mature granulomas.

The immunologic composition of granulomas was distinct from the pneumonia; granulomas are enriched for antimicrobial gene expression in both macrophages and T cells and show reduced bacterial antigen burden. In contrast, TREM2-expressing foamy macrophages are the predominant cell type occupying alveolar spaces in TB pneumonia with T cells infrequent. These TREM2⁺ macrophages exhibit a lipid-associated gene program, accumulate lipid droplets, and harbor Mycobacterium tuberculosis antigens and mRNA—corresponding to increased bacterial viability in vitro.