TREM2 <sup>+</sup> macrophages accumulate in alveoli of human pulmonary tuberculosis providing a permissive niche for bacterial growth

Rosane M. B. Teles(University of California, Los Angeles), Chaouki Benabdessalem(Institut Pasteur de Tunis), Jonathan Perrie(University of California, Los Angeles), Cenfu Wei(Northwestern University), Julie West(University of California, Los Angeles), Bruno Jorge de Andrade Silva(University of California, Los Angeles), Priscila R. Andrade(University of California, Los Angeles), Lilah A. Mansky(University of California, Los Angeles), Prajan Divakar(Bruker (United States)), Linda A. Fischbacher(Colorado State University), Karen Lam(University of California, Los Angeles), Feyiang Ma(University of California, Los Angeles), Yiqian Gu(University of California, Los Angeles), Kimia Rategh(University of California, Los Angeles), Madeline Brown(University of California, Los Angeles), Aparna Pillai(University of California, Los Angeles), Samuel W. French(Tunis University), Emna Romdhane(Tunis University), Mohamed-Ridha Barbouche(Washington University in St. Louis), Eynav Klechevsky(Washington University in St. Louis), Marco Colonna(Washington University in St. Louis), Adrie J. C. Steyn(University of California, Los Angeles), Steven J. Bensinger(University of California, Los Angeles), Daniel L. Barber(Tunis University), Soumaya Rammeh(Tunis University), Parambir S. Dulai(Northwestern University), Bryan D. Bryson(University of California, Los Angeles), Matteo Pellegrini(University of California, Los Angeles), John T. Belisle(Harvard University), Barry R. Bloom(Harvard University), Robert L. Modlin(University of California, Los Angeles)
bioRxiv (Cold Spring Harbor Laboratory)
July 18, 2025
10.1101/2025.07.15.664002
Cited by 0Open Access
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Abstract

Abstract Pulmonary tuberculosis (TB) exhibits marked spatial heterogeneity, with alveolar pneumonia and organized granulomas frequently coexisting within the same lung. While granulomas have long dominated conceptual models of TB pathogenesis, the immune programs operating within alveolar TB pneumonia in humans remain incompletely defined. Here, we integrate spatial transcriptomics, single-cell RNA sequencing, high-resolution imaging, and functional assays of human lung biopsies to directly compare alveolar pneumonia with adjacent granulomas from the same individuals. We demonstrate that alveolar TB pneumonia is enriched for TREM2⁺ lipid-laden macrophages characterized by lipid metabolic reprogramming, sparse T-cell infiltration, attenuated antimicrobial gene expression, and abundant Mycobacterium tuberculosis ( Mtb ) transcripts and antigens. In contrast, neighboring granulomas exhibit organized lymphoid architecture and robust antimicrobial programs. Mechanistically, the mycobacterial virulence lipid phthiocerol dimycocerosate (PDIM) and free mycolic acids induce TREM2 expression and activate TREM2–DAP12 signaling, promoting lipid droplet accumulation, suppressing autophagy, and enhancing intracellular Mtb survival in human macrophages. This immunometabolic state is pharmacologically reversible: 1,25-dihydroxyvitamin D₃ downregulates TREM2, restores autophagy, reduces lipid droplets, and limits bacterial viability. Together, these findings define a spatially localized TREM2⁺ foamy macrophage program within alveolar pneumonia that contrasts sharply with adjacent granulomatous immunity, establishing an niche permissive for bacillary persistence and potentially transmission, as well as identifying a tractable host pathway in human TB pathogenesis.

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