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Understanding mechanisms of pathogenesis and protection in human tuberculosis (TB) remain major global health challenges. While organized granulomas have long been the focus of TB research, growing evidence for asymptomatic transmission highlights the need to study earlier disease stages, particularly TB pneumonia, which remains underexplored. Defining the alveolar immune niche that governs bacillary expansion before granuloma formation is essential for interrupting transmission. Here, we integrate spatial transcriptomics, single cell RNA sequencing, and high resolution imaging of human lung biopsies to map early TB pneumonia and compare with adjacent granulomas within the same tissues. Pneumonic alveolar spaces were dominated by TREM2-associated macrophages, characterized by sparse T cell infiltration, minimal antimicrobial gene expression, and abundant antigens and transcripts. In contrast, granuloma cores were enriched for antimicrobial pathways, were surrounded by multiple cell types that walled off infection, and contained comparatively fewer bacterial markers. Our findings identify TREM2 positive 'foamy' macrophages as a key permissive alveolar niche for survival and growth. These cells represent an attractive target for early intervention to restrict infection and limit transmission. Early TB pneumonia defines an alveolar niche that fosters bacterial persistence and transmission before granuloma formation.

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.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.