DNA methylation predicts the outcome of COVID-19 patients with acute respiratory distress syndrome

Abstract

Background COVID-19 infections could be complicated by acute respiratory distress syndrome (ARDS), increasing mortality risk. We sought to assess the methylome of peripheral blood mononuclear cells in COVID-19 with ARDS. Methods We recruited 100 COVID-19 patients with ARDS under mechanical ventilation and 33 non-COVID-19 controls between April and July 2020. COVID-19 patients were followed at four time points for 60 days. DNA methylation and immune cell populations were measured at each time point. A multivariate cox proportional risk regression analysis was conducted to identify predictive signatures according to survival. Results The comparison of COVID-19 to controls at inclusion revealed the presence of a 14.4% difference in promoter-associated CpGs in genes that control immune-related pathways such as interferon-gamma and interferon-alpha responses. On day 60, 24% of patients died. The inter-comparison of baseline DNA methylation to the last recorded time point in both COVID-19 groups or the intra-comparison between inclusion and the end of follow-up in every group showed that most changes occurred as the disease progressed, mainly in the AIM gene, which is associated with an intensified immune response in those who recovered. The multivariate Cox proportional risk regression analysis showed that higher methylation of the “Apoptotic execution Pathway” genes (ROC1, ZNF789, and H1F0) at inclusion increases mortality risk by over twofold. Conclusion We observed an epigenetic signature of immune-related genes in COVID-19 patients with ARDS. Further, Hypermethylation of the apoptotic execution pathway genes predicts the outcome. Trial registration: IMRPOVIE study, NCT04473131.

Altered DNA methylation pattern contributes to differential epigenetic immune signaling in the upper respiratory airway of COVID-19 patients

“…There was a clear separation in the DNA methylation pattern in the airway samples between COVID-19 patients and healthy controls. The high impact exerted by COVID-19 on the DNA methylation pattern in the airway, is in line with other studies that explored this in blood samples from COVID-19 patients 15, 24, 25, 26, 27, 56 . Interestingly, patients who had undergone anti-inflammatory treatment such as oral/nasal inhalation glucocorticoids for previous/chronic airway manifestations had a different DNA methylation pattern and clustered with healthy controls in the PCA.…”

“…More recently, there have been multiple epigenetic studies aimed to unravel the complexities of SARS-CoV-2 pathogenesis and its enduring impact on the host 15, 16, 17 . Of the various epigenetic modifications, DNA alterations, particularly methylation, exhibit remarkable stability, and form an integral component of a cell’s programming, persisting throughout its life cycle and divisions.…”

Restoring the epigenetic landscape of lung microbiome: potential therapeutic approach for chronic respiratory diseases

“…Types of epigenetic changes include DNA methylation, histone modification, and miRNA regulation [ 15 – 17 ]. Epigenetics plays a crucial role in the relationship between the microbiome and lung disease [ 18 , 19 ]. The microbiome in the lungs is involved in regulating various biological processes such as cell proliferation, differentiation, stress response, and pathogenesis.…”

“…The microbiome in the lungs is involved in regulating various biological processes such as cell proliferation, differentiation, stress response, and pathogenesis. Studies have shown that certain microRNAs are dysregulated in chronic lung diseases such as COPD, IPF, and CF and may contribute to the development and progression of these diseases by regulating inflammation, cell proliferation, tissue remodeling, and the immune response to infection [ 14 , 17 , 18 , 20 ].…”

“…This mucus not only offers a supportive structure and a nutrient-rich habitat for the bacterium to thrive but also rarely comes into direct contact with the underlying airway epithelial cells [ 23 ]. The presence of Pseudomonas in the respiratory tract can disrupt the composition of the respiratory microbiome, resulting in alterations to its typical functions and an elevated susceptibility to respiratory infections [ 18 , 24 ]. Studies have also shown that Pseudomonas can impact the epigenetic regulation of host cells.…”