Mycobacterium tuberculosis preferentially infects specific macrophage subsets in primate granulomas during the early stages of tuberculosis.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and defined by formation of granulomas, immune aggregates that can restrict or support bacterial replication. Macrophages are fundamental components of granulomas and TB pathogenesis, yet their population structure and functional diversity is incompletely understood. The interaction between macrophages and Mtb in vivo, including which cell subsets are infected and how they respond to colonization, is a major determinant of disease outcome. Here, we profiled lung tissue and granulomas from Mtb-infected cynomolgus macaques, an animal model that closely recapitulates human TB, to define macrophage biology in the early stage of infection. We identified distinct subsets, including embryonic-origin tissue resident alveolar macrophages (AMs), monocyte-derived AMs, and interstitial macrophages with distinct spatial localization in granulomas. Tissue-resident AMs and a novel macrophage subset undergoing epithelial-to-mesenchymal transition were the most frequently infected cells in lung tissue. Mtb-infected cells specifically expressed immune-related and migration-associated genes, suggesting that Mtb induces or exploits these pathways in early infection as a survival strategy in vivo. Our findings highlight the complex interplay between macrophage heterogeneity and functional states that serve as a driver of susceptibility to Mtb infection and TB progression.