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

Journal article

Highlights: What are the main findings? COVID-19 patients show a unique DNA methylation profile in the upper airway, with over 510,000 differentially methylated CpGs affecting antiviral, interferon, and immune response genes. Some methylation changes are temporary, normalizing after 6 weeks, while key immune regulators (e.g., IL17A, ERK1/2, OAS1, MX1) remain significantly involved. What is the implication of the main finding? SARS-CoV-2 may reprogram immune and repair pathways in the airways, influencing recovery and susceptibility to future respiratory infections. These findings provide potential targets for biomarkers and therapeutic strategies to modulate post-COVID-19 airway health. Abstract: 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.

Authors: Govender, M; Das, J; Hopkins, FR; Svanberg, C; Nordgren, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Cells
• Volume: 14
• Issue: 21
• Pages: 1673
• Article number: 1673
• Publication date: 2025-10-27
• Acceptance date: 2025-10-20
• DOI: 10.3390/cells14211673
• EISSN: 2073-4409
• ISSN: 2073-4409
• Language: English
• Keywords: nasopharyngeal; epigenetic; airway; DNA methylation; unvaccinated COVID-19 patients; COVID-19 patients