ABSTRACT
BackgroundEpigenetic alterations upon microbial challenge have been described as both a defence strategy and a result of pathogenic manipulation. While most COVID-19 studies focus on inflammatory and immune-mediated responses, little is known about epigenetic modifications in response to SARS-CoV-2 infection. MethodsEpigenome-wide DNA methylation patterns from COVID-19 convalescents were compared to uninfected controls from before and after the pandemic. Peripheral blood mononuclear cell (PBMC) DNA was extracted from uninfected controls, COVID-19 convalescents and symptom-free individuals with SARS-CoV-2-specific T cell-responses, as well as from PBMCs stimulated in vitro with SARS-CoV-2. Subsequently, the Illumina MethylationEPIC 850K array was performed, and statistical/bioinformatic analyses comprised differential DNA methylation, pathway over-representation and module identification analyses. ResultsDifferential DNA methylation patterns distinguished COVID-19 convalescents from uninfected controls, with similar results in an experimental SARS-CoV-2 infection model. A SARS-CoV-2-induced module was identified in vivo, comprising 66 genes of which six (TP53, INS, HSPA4, SP1, ESR1 and FAS) were present in corresponding in vitro analyses. Over-representation analyses revealed involvement in Wnt, muscarinic acetylcholine receptor signalling and gonadotropin-releasing hormone receptor pathways. Furthermore, numerous differentially methylated and network genes from both settings interacted with the SARS-CoV-2 interactome. ConclusionsAltered DNA methylation patterns of COVID-19 convalescents suggest recovery from mild-to-moderate SARS-CoV-2 infection leaves longstanding epigenetic traces. As in vitro SARS-CoV-2 infection corroborated in vivo exposure results, this indicates DNA methylation is involved in immune cell responses to challenge with this virus. Future studies should determine whether this reflects host-induced protective antiviral defence or targeted viral hijacking to evade host defence.
