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

Tuberculosis (TB) remains a major global health challenge. While organized granulomas have long been the focus of TB pathogenesis research, the early development of TB pneumonia typically preceding granuloma formation 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. We further show that the M. tuberculosis virulence lipids, PDIM and mycolic acids, potently induce and activate TREM2 signaling in TREM2-expressing macrophages, promoting an intracellular environment permissive for bacterial growth. These findings establish TREM2⁺ macrophages as an early niche for M. tuberculosis survival and implicate TB pneumonia as a critical stage in disease transmission. Targeting this foamy macrophage population may offer opportunities to interrupt early TB progression and transmission.