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Characteristically, as Mycobacterium tuberculosis replicates within macrophages, the granuloma enlarges, and then the center undergoes necrosis, promoting mycobacterial growth in the debris (caseum). This sequence results in large, mycobacterium-rich granulomas that can rupture into airways, facilitating disease transmission. Here, using the zebrafish-Mycobacterium marinum tuberculosis model, we find that both stages \u2013 granuloma enlargement and necrosis \u2013 depend on the mycobacterial virulence factor, EsxA, that induces mitochondrial damage and apoptosis of infected macrophages. Initially, dying macrophages are engulfed by newly recruited macrophages. Then, the enlarging granuloma core becomes hypoxic and induces Hypoxia Inducible Factor-1 (HIF-1). HIF-1 suppresses mitochondrial respiration, sensitizing macrophages to EsxA mitotoxicity. These sensitized macrophages undergo accelerated apoptosis which outstrips clearance, causing mycobacterium-rich necrotic debris to accumulate in the granuloma cores. Thus, tuberculosis transmission depends on the dynamic interplay between a mycobacterial virulence factor and an adaptive host metabolic program.<\/jats:p>","DOI":"10.64898\/2026.02.06.702658","type":"posted-content","created":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T03:30:14Z","timestamp":1770521414000},"source":"Crossref","is-referenced-by-count":0,"title":["Macrophage adaptation to hypoxia in the tuberculous granuloma potentiates mycobacterium-induced mitochondrial damage and granuloma necrosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0280-1800","authenticated-orcid":false,"given":"Antonio J.","family":"Pag\u00e1n","sequence":"first","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"},{"name":"Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingnan","family":"Lyu","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2043-0502","authenticated-orcid":false,"given":"Michal","family":"Eisenberg-Bord","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6450-744X","authenticated-orcid":false,"given":"Elisabeth M.","family":"Busch-Nentwich","sequence":"additional","affiliation":[{"name":"School of Biological and Behavioural Sciences, Faculty of Science and Engineering, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0692-5533","authenticated-orcid":false,"given":"Lalita","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026021105504993000_2026.02.06.702658v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-100022"},{"key":"2026021105504993000_2026.02.06.702658v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3211"},{"key":"2026021105504993000_2026.02.06.702658v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.11.014"},{"key":"2026021105504993000_2026.02.06.702658v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.06.011"},{"key":"2026021105504993000_2026.02.06.702658v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.013"},{"key":"2026021105504993000_2026.02.06.702658v1.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.150227197"},{"key":"2026021105504993000_2026.02.06.702658v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1781"},{"key":"2026021105504993000_2026.02.06.702658v1.8","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a018499"},{"key":"2026021105504993000_2026.02.06.702658v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30148-1"},{"key":"2026021105504993000_2026.02.06.702658v1.10","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201311-2106PP"},{"key":"2026021105504993000_2026.02.06.702658v1.11","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.2013.78.023283"},{"key":"2026021105504993000_2026.02.06.702658v1.12","doi-asserted-by":"crossref","unstructured":"Canetti, G . 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