{ "abstract": "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 in vitro 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-κB-dependent inflammatory signature associated with disease severity, both in monocytes from COVID-19 patients and in MDMs infected in vitro. 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 in vitro 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-κB/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.", "abstract_shown": true, "affiliations": [ "Grupo Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia", "Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia", "Grupo de Inmunología Celular e Inmunogenética (GICIG), Facultad de Medicina y Unidad de Citometría, Sede de Investigación Universitaria, Universidad de Antioquia, Medellín, Colombia" ], "article_type": "Research Article", "arxiv": null, "author_total": 9, "authors": [ { "affs": [ 0 ], "name": "Juan Felipe Valdés-López" }, { "affs": [ 1 ], "name": "Diana di Filippo" }, { "affs": [ 2 ], "name": "Sharon Penagos" }, { "name": "Lady Johana Hernández-Sarmiento" }, { "name": "Johanna C. Arroyave-Ospina" }, { "name": "Mauricio Rojas" }, { "name": "Silvio Urcuqui-Inchima" }, { "name": "Wbeimar Aguilar-Jiménez" }, { "name": "Maria-Cristina Navas" } ], "bibtex": "https://research.draconitic.com/paper/9bgd2tn8rphq9.bib", "cited_by": 0, "doi": "10.1371/journal.pone.0357030", "fulltext_url": null, "id": "9bgd2tn8rphq9", "issns": [ "1932-6203" ], "landing_url": "https://doi.org/10.1371/journal.pone.0357030", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2734|Vitamin D Research Studies" ], [ "plos", "/Biology and life sciences/Biochemistry/Hormones/Lipid hormones/Calcitriol" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Monocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Biology and life sciences/Developmental biology/Molecular development/Cytokines" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Biology and life sciences/Immunology/Immune system/Innate immune system/Cytokines" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Coronaviruses/SARS coronavirus/SARS CoV 2" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Coronaviruses/SARS coronavirus/SARS CoV 2" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Coronaviruses/SARS coronavirus/SARS CoV 2" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Cytokines" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Monocytes" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system/Innate immune system/Cytokines" ], [ "plos", "/Medicine and health sciences/Medical conditions/Infectious diseases/Viral diseases/COVID 19" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Coronaviruses/SARS coronavirus/SARS CoV 2" ], [ "plos", "/Physical sciences/Chemistry/Chemical compounds/Organic compounds/Vitamins/Vitamin D" ], [ "plos", "/Physical sciences/Chemistry/Organic chemistry/Organic compounds/Vitamins/Vitamin D" ] ], "openalex": "W7212260355", "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0357030&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-11", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/9bgd2tn8rphq9.ris", "sources": [ { "first_seen": "2026-10-30T12:17:56Z", "native_id": "10.1371/journal.pone.0357030", "source": "plos", "url": "https://doi.org/10.1371/journal.pone.0357030" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" } ], "title": "SARS-CoV-2 infection induces functional impairment of vitamin D receptor signaling to drive interleukin 6-dependent hyperinflammation in mononuclear phagocytes", "title_text": "SARS-CoV-2 infection induces functional impairment of vitamin D receptor signaling to drive interleukin 6-dependent hyperinflammation in mononuclear phagocytes", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:56Z", "url": "https://research.draconitic.com/paper/9bgd2tn8rphq9", "venue": "PLOS One", "versions": [] }