{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:17:06Z","timestamp":1793398626110,"version":"4.5.0"},"reference-count":129,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The hallmark tissue lesions of tuberculosis (TB) are granulomas. These multicellular structures exhibit varying degrees of cellular complexity, are dynamic, and show considerable diversity within and between hosts. Categorization based on gross pathologic features, particularly caseation and necrosis, was historically coined prior to the identification of mycobacteria as the causative agent of TB. More recently, granuloma zonation based on immune cell composition, metabolite abundance, and physical characteristics has gained attention. With the advent of single-cell analyses, distinct microenvironments and cellular ecosystems within TB granulomas have been identified. We summarize the architecture of TB granulomas and highlight their cellular heterogeneity, including cell niches as well as physical factors such as oxygen gradients that modulate lesion fate. We discuss opportunities for therapy, highlighting new models and the power of\n                    <jats:italic>in silico<\/jats:italic>\n                    modeling to unravel granuloma features and trajectories. Understanding the relevance of the granuloma microenvironment to disease pathophysiology will facilitate the development of more effective interventions, such as host-directed therapies for TB.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1575133","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T06:16:42Z","timestamp":1742797002000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Microenvironments of tuberculous granuloma: advances and opportunities for therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Gesa","family":"Krueger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shah","family":"Faisal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca","family":"Dorhoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"B1","volume-title":"Global tuberculosis report 2024","year":"2024"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/path.v208:2","article-title":"New insights into the function of granulomas in human tuberculosis","volume":"208","author":"Ulrichs","year":"2006","journal-title":"J Pathol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2010.00994.x","article-title":"For better or for worse: the immune response against Mycobacterium tuberculosis balances pathology and protection","volume":"240","author":"Dorhoi","year":"2011","journal-title":"Immunol Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20221392","article-title":"Spatial mapping reveals granuloma diversity and histopathological superstructure in human tuberculosis","volume":"220","author":"Sawyer","year":"2023","journal-title":"J Exp Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-015-0534-0","article-title":"Immunometabolism within the tuberculosis granuloma: amino acids, hypoxia, and cellular respiration","volume":"38","author":"Qualls","year":"2016","journal-title":"Semin Immunopathol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cell.2008.11.014","article-title":"The role of the granuloma in expansion and dissemination of early tuberculous infection","volume":"136","author":"Davis","year":"2009","journal-title":"Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nrd.2017.162","article-title":"Host-directed therapies for bacterial and viral infections","volume":"17","author":"Kaufmann","year":"2018","journal-title":"Nat Rev Drug Discovery"},{"key":"B8","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1111\/imr.2015.264.issue-1","article-title":"Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses","volume":"264","author":"Lenaerts","year":"2015","journal-title":"Immunol Rev"},{"key":"B9","volume-title":"The Tubercle Bacillus in the Pulmonary Lesion of Man","author":"Canetti","year":"1955"},{"key":"B10","volume-title":"Lectures on the Comparative Pathology of Inflammation, delivered at the Pasteur Instutute in 1891","author":"Elie","year":"1893"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1223260","article-title":"Animal models for COVID-19 and tuberculosis","volume":"14","author":"Corleis","year":"2023","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0021-9975(98)80069-8","article-title":"Early lesion formation in cattle experimentally infected with Mycobacterium bovis","volume":"119","author":"Cassidy","year":"1998","journal-title":"J Comp Pathol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1016\/j.immuni.2022.04.004","article-title":"Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control","volume":"55","author":"Gideon","year":"2022","journal-title":"Immunity"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2023.1264200","article-title":"Characterisation and development of histopathological lesions in a Guinea pig model of Mycobacterium tuberculosis infection","volume":"10","author":"Larenas-Munoz","year":"2023","journal-title":"Front Vet Sci"},{"key":"B15","article-title":"Macrophage accumulation, division, maturation, and digestive and microbicidal capacities in tuberculous lesions. 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