{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:10:02Z","timestamp":1789150202664,"version":"build-2803163510"},"reference-count":76,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad de Antioquia-CODI","award":["Acta No. 2020-34832"],"award-info":[{"award-number":["Acta No. 2020-34832"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    The dysregulated inflammatory response, particularly the interleukin 6 (IL-6)-driven cytokine storm, is a hallmark of severe COVID-19. Mononuclear phagocytes are key cellular populations in the pathogenesis of SARS-CoV-2 infection, but the underlying regulatory mechanisms remain incompletely defined. Based on existing evidence of vitamin D immunomodulatory properties in viral infections, we investigated its role during SARS-CoV-2 infection. We integrated transcriptional profiling of monocytes and myeloid dendritic cells (mDCs) from healthy individuals and COVID-19 patients (moderate\/severe, with\/without viremia) with an\n                    <jats:italic>in vitro<\/jats:italic>\n                    model of SARS-CoV-2-infected monocyte-derived macrophages (MDMs). Additionally, a functional assay using U937-derived monocytes and macrophages challenged with inactivated SARS-CoV-2 particles was used to assess the immunomodulatory effect of calcitriol (vitamin D) treatment. We found that SARS-CoV-2 infection triggers an NF-\u03baB-dependent inflammatory signature associated with disease severity, both in monocytes from COVID-19 patients and in MDMs infected\n                    <jats:italic>in vitro<\/jats:italic>\n                    . This signature is characterized by hyperproduction of IL-6 and upregulation of its signaling components, including IL6R, JAK1\/2, STAT3, and SOCS3. Moreover, we found some evidence of a novel viral-dependent suppression of the Vitamin D Receptor (VDR) pathway, demonstrated by downregulation of both VDR expression and its target genes, including CAMP, LYZ, and IRF5, in monocytes from patients with COVID-19 and\n                    <jats:italic>in vitro<\/jats:italic>\n                    SARS-CoV-2-infected MDMs. This resulted in functional impairment of VDR signaling. Importantly, calcitriol treatment potently suppressed SARS-CoV-2-induced IL-6 production in our model of U937 cell line, suggesting that restoration of VDR signaling could temper this key inflammatory axis. Our findings reveal a dual-hit mechanism in severe COVID-19, in which SARS-CoV-2 infection simultaneously hyperactivates the pro-inflammatory pattern-recognition receptors\/NF-\u03baB\/IL-6 axis and suppresses the anti-inflammatory VDR pathway in mononuclear phagocytes. The effective inhibition of IL-6 by calcitriol provides a potential role of vitamin D in mitigating pathological inflammation, positioning it as a plausible immunomodulatory strategy for severe COVID-19.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0357030","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:37:31Z","timestamp":1789148251000},"page":"e0357030","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["SARS-CoV-2 infection induces functional impairment of vitamin D receptor signaling to drive interleukin 6-dependent hyperinflammation in mononuclear phagocytes"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3691-4501","authenticated-orcid":true,"given":"Juan Felipe","family":"Vald\u00e9s-L\u00f3pez","sequence":"first","affiliation":[{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Gastrohepatolog\u00eda, Facultad de Medicina"]},{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Inmunovirolog\u00eda, Facultad de Medicina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"di Filippo","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Gastrohepatolog\u00eda, Facultad de Medicina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Penagos","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Gastrohepatolog\u00eda, Facultad de Medicina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3733-3488","authenticated-orcid":true,"given":"Lady Johana","family":"Hern\u00e1ndez-Sarmiento","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Inmunovirolog\u00eda, Facultad de Medicina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna C.","family":"Arroyave-Ospina","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Gastrohepatolog\u00eda, Facultad de Medicina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7791-9328","authenticated-orcid":true,"given":"Mauricio","family":"Rojas","sequence":"additional","affiliation":[{"name":"Sede de Investigaci\u00f3n Universitaria, Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo de Inmunolog\u00eda Celular e Inmunogen\u00e9tica (GICIG), Facultad de Medicina y Unidad de Citometr\u00eda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio","family":"Urcuqui-Inchima","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Inmunovirolog\u00eda, Facultad de Medicina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0790-055X","authenticated-orcid":true,"given":"Wbeimar","family":"Aguilar-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Inmunovirolog\u00eda, Facultad de Medicina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2610-9306","authenticated-orcid":true,"given":"Maria-Cristina","family":"Navas","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia","place":["Medell\u00edn, Colombia"],"department":["Grupo Gastrohepatolog\u00eda, Facultad de 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