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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Visceral leishmaniasis, caused by Leishmania donovani, is characterized by profound alterations in hepatic immune responses that promote parasite persistence. However, the lack of physiologically relevant in vitro systems limits investigation of tissue-level host\u2013pathogen interactions. An immunocompetent three-dimensional hepatic organoid model incorporating bone marrow-derived macrophages was established to investigate liver-stage immune responses to L. donovani infection. Integrated cytokine profiling and transcriptomic analyses were benchmarked against infected mouse liver tissue. Macrophages acquired functional characteristics consistent with a Kupffer cell-like phenotype and contributed to immune homeostasis within the co-culture. Infection induced a conserved immune response characterized by inflammatory and chemotactic activation. This response was accompanied by coordinated suppression of antimicrobial pathways, including the IL-12\u2013IFN-\u03b3 axis and interferon-stimulated genes. These immune alterations were largely shared between the organoid model and infected liver tissue, although systemic metabolic reprogramming and multicellular complexity were not fully recapitulated. Our findings identify a conserved pattern of hepatic immune dysregulation in which inflammatory activation is uncoupled from effective antimicrobial signaling, potentially facilitating parasite persistence. This immunocompetent hepatic organoid platform provides a physiologically relevant system for investigating host\u2013pathogen interactions and evaluating host-directed therapeutic strategies for visceral leishmaniasis.<\/jats:p>","DOI":"10.3390\/ijms27167178","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T11:51:36Z","timestamp":1786449096000},"page":"7178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Immunocompetent Hepatic Organoid Model Reveals Conserved Hepatic Immune Dysregulation During Leishmania donovani Infection"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1069-3940","authenticated-orcid":false,"given":"Mar\u00eda-Cristina","family":"Gonz\u00e1lez-Montero","sequence":"first","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0042-962X","authenticated-orcid":false,"given":"Miguel","family":"Criado","sequence":"additional","affiliation":[{"name":"Instituto de Ganader\u00eda de Monta\u00f1a, CSIC-Universidad de Le\u00f3n, Finca Marzanas s\/n, Grulleros, 24346 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5254-8121","authenticated-orcid":false,"given":"Celia","family":"Fern\u00e1ndez-Rubio","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2361-3785","authenticated-orcid":false,"given":"Yolanda","family":"P\u00e9rez-Pertejo","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"},{"name":"Instituto de Biomedicina (IBIOMED), Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"},{"name":"IBIOLE\u00d3N (Instituto de Investigaci\u00f3n Biosanitaria de Le\u00f3n), Hospital de Le\u00f3n, Altos de Nava s\/n, 24071 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9148-2997","authenticated-orcid":false,"given":"Rosa M.","family":"Reguera","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"},{"name":"Instituto de Biomedicina (IBIOMED), Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"},{"name":"IBIOLE\u00d3N (Instituto de Investigaci\u00f3n Biosanitaria de Le\u00f3n), Hospital de Le\u00f3n, Altos de Nava s\/n, 24071 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0418-6116","authenticated-orcid":false,"given":"Rafael","family":"Bala\u00f1a-Fouce","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"},{"name":"Instituto de Biomedicina (IBIOMED), Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"},{"name":"IBIOLE\u00d3N (Instituto de Investigaci\u00f3n Biosanitaria de Le\u00f3n), Hospital de Le\u00f3n, Altos de Nava s\/n, 24071 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5617-9669","authenticated-orcid":false,"given":"Carlos","family":"Garc\u00eda-Estrada","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Facultad de Veterinaria, Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"},{"name":"Instituto de Biomedicina (IBIOMED), Universidad de Le\u00f3n, Campus de Vegazana s\/n, 24007 Le\u00f3n, Spain"},{"name":"IBIOLE\u00d3N (Instituto de Investigaci\u00f3n Biosanitaria de Le\u00f3n), Hospital de Le\u00f3n, Altos de Nava s\/n, 24071 Le\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev-immunol-051116-052415","article-title":"Immune responses in the liver","volume":"36","author":"Kubes","year":"2018","journal-title":"Annu. 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