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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\u207a lipid-laden macrophages characterized by lipid metabolic reprogramming, sparse T-cell infiltration, attenuated antimicrobial gene expression, and abundant\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (\n                  <jats:italic>Mtb<\/jats:italic>\n                  ) 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\u2013DAP12 signaling, promoting lipid droplet accumulation, suppressing autophagy, and enhancing intracellular\n                  <jats:italic>Mtb<\/jats:italic>\n                  survival in human macrophages. This immunometabolic state is pharmacologically reversible: 1,25-dihydroxyvitamin D\u2083 downregulates TREM2, restores autophagy, reduces lipid droplets, and limits bacterial viability. Together, these findings define a spatially localized TREM2\u207a 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.\n                <\/jats:p>","DOI":"10.1101\/2025.07.15.664002","type":"posted-content","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T17:35:13Z","timestamp":1752860113000},"source":"Crossref","is-referenced-by-count":0,"title":["TREM2\n                  <sup>+<\/sup>\n                  macrophages accumulate in alveoli of human pulmonary tuberculosis providing a permissive niche for bacterial growth"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2908-3244","authenticated-orcid":false,"given":"Rosane M. B.","family":"Teles","sequence":"first","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaouki","family":"Benabdessalem","sequence":"additional","affiliation":[{"name":"Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Perrie","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell, and Developmental Biology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cenfu","family":"Wei","sequence":"additional","affiliation":[{"name":"Northwestern University, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"West","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno J.","family":"de Andrade Silva","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priscila R.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilah A.","family":"Mansky","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prajan","family":"Divakar","sequence":"additional","affiliation":[{"name":"Bruker Spatial Biology, Bothell, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Fischbacher","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4635-7008","authenticated-orcid":false,"given":"Karen","family":"Lam","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feiyang","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiqian","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell, and Developmental Biology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimia","family":"Rategh","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeline","family":"Brown","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aparna","family":"Pillai","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel M.","family":"French","sequence":"additional","affiliation":[{"name":"Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emna","family":"Romdhane","sequence":"additional","affiliation":[{"name":"Department of Pathology, Charles Nicolle Hospital, Tunis, Tunisia; LR23ES02, Facult\u00e9 de M\u00e9decine de Tunis, Universit\u00e9 de Tunis El Manar, Tunis, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed-Ridha","family":"Barbouche","sequence":"additional","affiliation":[{"name":"Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eynav","family":"Klechevsky","sequence":"additional","affiliation":[{"name":"Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, MO, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5222-4987","authenticated-orcid":false,"given":"Marco","family":"Colonna","sequence":"additional","affiliation":[{"name":"Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, MO, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrie J. 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