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

## TL;DR

Unvaccinated COVID-19 patients show long-lasting DNA methylation changes in their upper airway, affecting immune genes and potentially influencing future respiratory health.

## Contribution

The study identifies specific DNA methylation changes in the upper airway of hospitalized COVID-19 patients and links them to immune and repair pathways.

## Key findings

- Over 510,000 differentially methylated CpGs were found in the upper airway of COVID-19 patients.
- Methylation changes in genes like IL17A, ERK1/2, OAS1, and MX1 suggest lasting immune impacts.
- Some methylation patterns normalized after 6 weeks, but key immune regulators remained affected.

## Abstract

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.

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.