Altered DNA Methylation Pattern Contributes to Differential Epigenetic Immune Signaling in the Upper Respiratory Airway of Unvaccinated COVID-19 Patients

DOI record: { "DOI": "10.3390/cells14211673", "ISSN": [ "2073-4409" ], "URL": "http://dx.doi.org/10.3390/cells14211673", "abstract": "<jats:p>SARS-CoV-2 infection remains a global health concern, with its impact on host immune responses not fully understood. In a case–control study, we examined how COVID-19 affects DNA methylation patterns in the upper respiratory airway of hospitalized individuals. DNA methylation arrays were performed on nasopharyngeal samples at inclusion/hospitalization and 6 weeks post-inclusion. We found a distinct DNA methylation pattern in COVID-19 patients compared to healthy controls, identifying 510,099 differentially methylated CpGs. Within the transcription start sites (TSSs) and gene body, COVID-19 patients displayed a higher number of genes/CpGs with elevated methylation levels. Enrichment analysis of TSS-methylated genes revealed effects of SARS-CoV-2 on genes associated with type I interferons, anti-viral and inflammatory responses, and immune functions. Some CpG methylations were transient, and normalized at group level by 6 weeks post-inclusion. Several IFN-regulated genes, including OAS1, OAS3, IFIT3, and MX1, were identified. Among the top regulators were IL17A and ERK1/2, both involved in inflammatory processes. Networks nodes included IGF1 and EGF, associated with processes including tissue repair and activation of immune responses. Overall, our data suggests that COVID-19 can impact the upper airway by modifying gene methylation patterns. This could have implications for conditioning of the airways, how individuals respond to future airway infections, and therapeutic interventions.</jats:p>", "alternative-id": [ "cells14211673" ], "author": [ { "ORCID": "https://orcid.org/0000-0001-8327-5517", "affiliation": [ { "name": "Division of Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" }, { "name": "Centre for Human Genetics, Pandemic Sciences Institute, University of Oxford, Oxford OX3 7BN, UK" } ], "authenticated-orcid": false, "family": "Govender", "given": "Melissa", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0002-5649-4658", "affiliation": [ { "name": "Bioinformatics, Core Facility, Division of Cell Biology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, 581 85 Linköping, Sweden" }, { "name": "Clinical Genomics Linköping, SciLife Laboratory, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" } ], "authenticated-orcid": false, "family": "Das", "given": "Jyotirmoy", "sequence": "additional" }, { "affiliation": [ { "name": "Division of Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" } ], "family": "Hopkins", "given": "Francis R.", "sequence": "additional" }, { "affiliation": [ { "name": "Division of Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" } ], "family": "Svanberg", "given": "Cecilia", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-5349-2569", "affiliation": [ { "name": "Division of Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" } ], "authenticated-orcid": false, "family": "Nordgren", "given": "Johan", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-9770-4623", "affiliation": [ { "name": "Division of Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" } ], "authenticated-orcid": false, "family": "Hagbom", "given": "Marie", "sequence": "additional" }, { "affiliation": [ { "name": "Division of Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" } ], "family": "Klingström", "given": "Jonas", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-5719-5601", "affiliation": [ { "name": "Division of Infection and Inflammation, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" }, { "name": "Department of Infectious Diseases, Vrinnevi Hospital, 603 79 Norrköping, Sweden" } ], "authenticated-orcid": false, "family": "Nilsdotter-Augustinsson", "given": "Åsa", "sequence": "additional" }, { "affiliation": [ { "name": "Laboratory Centre, Xiamen University Malaysia, Sepang 43900, Selangor, Malaysia" } ], "family": "Yong", "given": "Yean K.", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-4238-1924", "affiliation": [ { "name": "Laboratory Medicine, Department of Pathology, School of Medicine, Emory University, Atlanta, GA 30322, USA" }, { "name": "Division of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA" } ], "authenticated-orcid": false, "family": "Velu", "given": "Vijayakumar", "sequence": "additional" }, { "affiliation": [ { "name": "State Public Health Laboratory, Directorate of Public Health and Preventive Medicine, DMS Campus, Teynampet, Chennai 600 018, Tamil Nadu, India" } ], "family": "Raju", "given": "Sivadoss", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-5622-866X", "affiliation": [ { "name": "Division of Infection and Inflammation, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" }, { "name": "Department of Infectious Diseases, Vrinnevi Hospital, 603 79 Norrköping, Sweden" } ], "authenticated-orcid": false, "family": "Sjöwall", "given": "Johanna", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-7866-9818", "affiliation": [ { "name": "Infection and Inflammation, Department of Biotechnology, Central University of Tamil Nadu, Thiruvarur 610 005, Tamil Nadu, India" } ], "authenticated-orcid": false, "family": "Shankar", "given": "Esaki M.", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-0145-4966", "affiliation": [ { "name": "Division of Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" }, { "name": "Department of Clinical Immunology and Transfusion Medicine, Linköping University, 583 30 Linköping, Sweden" } ], "authenticated-orcid": false, "family": "Nyström", "given": "Sofia", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-4524-0177", "affiliation": [ { "name": "Division of Molecular Medicine and Virology, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden" } ], "authenticated-orcid": false, "family": "Larsson", "given": "Marie", "sequence": "additional" } ], "container-title": "Cells", "container-title-short": "Cells", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2025, 10, 28 ] ], "date-time": "2025-10-28T11:47:19Z", "timestamp": 1761652039000 }, "deposited": { "date-parts": [ [ 2025, 10, 29 ] ], "date-time": "2025-10-29T05:33:27Z", "timestamp": 1761716007000 }, "funder": [ { "DOI": "10.13039/501100004359", "award": [ "201701091" ], "award-info": [ { "award-number": [ "201701091" ] } ], "doi-asserted-by": "crossref", "id": [ { "asserted-by": "crossref", "id": "10.13039/501100004359", "id-type": "DOI" } ], 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