Early Human Pulmonary Lesions Define a Permissive Alveolar Niche for Mycobacterium tuberculosis

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 Mycobacterium tuberculosis 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 M. tuberculosis survival and growth. These cells represent an attractive target for early intervention to restrict infection and limit transmission.