Methylation patterns of the nasal epigenome of hospitalized SARS-CoV-2 positive patients reveal insights into molecular mechanisms of COVID-19

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a pandemic with variable presentations ranging from asymptomatic to death. Efforts to identify factors responsible for differential COVID-19 severity have largely been approached through genome wide association studies (GWAS) and transcriptomic analysis. More recently, variability in host epigenomics has garnered attention as a cause of disease severity. However, whole epigenome analysis of the target tissues (i.e., respiratory tract) in SARS-CoV-2 infection remains ill-defined. We interrogate the nasal methylome to identify pathophysiologic drivers in COVID-19 severity through whole genome bisulfite sequencing (WGBS) of nasal swabs from severely versus mildly affected COVID-19 positive individuals. In severe as compared to mild COVID-19 patients, we noted differential methylation in intergenic regions and low methylated regions (LMRs), demonstrating the importance of distal regulatory elements in COVID-19. Additionally, we demonstrated differential methylation of pathways implicated in immune cell recruitment and function, and the inflammatory response. We find significant hypermethylation (downregulation) of the FUT4 promoter implicating impaired neutrophil adhesion in severe disease. We also identify hypermethylation of ELF5 binding sites suggesting downregulation of ELF5 targets in the nasal cavity as a factor in COVID-19 phenotypic variability. This study demonstrates methylation is a critical driver in the immune response to SARS-CoV-2 infection, with enhancer-like elements and distal regulatory regions playing especially important roles. These differences in the nasal methylome contribute to disease severity through differential immune cell recruitment and function, dysfunction innate and adaptive immunity, and differential regulation of the inflammatory response.