A methylation clock model of mild SARS‐CoV‐2 infection provides insight into immune dysregulation.

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS‐CoV‐2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow‐up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation‐based machine learning models that distinguished samples from pre‐, during‐, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS‐CoV‐2 infection to the model‐defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS‐CoV‐2 epigenetic landscape we identify is antiprotective. Synopsis: Characterization of the temporal dynamics of blood methylation changes in young adults following asymptomatic and mild SARS‐CoV‐2 infection brings insights into the long‐term memory of environmental exposure and potential disease associations.Both symptomatic and asymptomatic infections induce methylation changes that are not always associated with gene expression changes.Methylation changes persist for longer than gene expression changes.The complex dynamics of methylation alterations can be used to predict the timing of infection.Contrary to the trained immunity phenomenon, the presence of a post‐infection‐like methylation state at baseline is anti‐protective for subsequent SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]