Maternal environmental exposures, including viral infections, can exert intergenerational effects on the offspring’s epigenome. Herein, based on the Swedish COVID-19 during Pregnancy and Early childhood study (COPE), we explored how mild SARS-CoV-2 infection during pregnancy affected the DNA methylome of peripheral blood mononuclear cells in infants, using Illumina EPIC array. We found significant alterations in DNA methylation patterns in genes related to neurodevelopmental pathways that overlap with cellular processes hijacked by viruses for their own replication. The alterations were further confirmed in cord blood mononuclear cells. Subsequently, we determined the functional consequences of epigenetic rewiring due to maternal SARS-CoV-2 infection without fetal infection and found that fetal exposure to mediators driven by maternal infection, results in an altered responsiveness of the infant’s immune cells upon subsequent cell activation in vitro. Finally, we demonstrate that these functional alterations were linked to the identified DNA methylation changes.

M.L. and S.S. are founders of a company, which has the ambition to develop DNAm-based biomarkers for a variety of conditions, including Post-COVID Conditions. The other authors declare no competing interests.

The initiation of the COPE study was financed by the Simons Foundation Autism Research Initiative, SFARI (V.S., 863675), Jane and Dan Olsson Foundation (V.S., 2021-02), Stiftelsen Erik & Lily Philipsons minnesfond (V.S., dnr 98) and Swedish Research Council grants (H.B., 2018-00470; S.B.W., 2016-00526). This substudy of the COPE study was supported by Swedish Heart Lung Foundation (M.L., 20220034), Swedish Research Council (A.R., 4.3-2019-00201 & GD-2020-138; T.A., 2020-01111; M.L., 2021-03183 & 2022-01213); Johanna Cocozza foundation (T.A.), Swedish Cancer Society (A.R., 211832Pj01H2/Infection-Autoimmunity-B-lymphoma grant) and local Linköping University funds. 

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Swedish Ethical Review Authority (dnr 2020-02189 and amendments 2020-02848, 2020-05016, 2020-06696, and 2021-00870) gave ethical approval for this work and received national biobank approval by the Biobank Väst (dnr B2000526:970).

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↵* Shared first authorship

↵# Shared last authorship

Lead contact: Maria Lerm

The datasets generated during the current study are not publicly available due to ethical dilemmas in traceability of DNA methylation data, but processed data that is pseudonymized and depleted of genetic variant information (beta matrixes with Illumina probe IDs and beta values) will be available upon request through the Federated European Genome-phenome Archive (FEGA) Sweden controlled-access repository, upon publication. Bioinformatic pipelines used to analyze the data and to generate graphs and figures will be available on the following GitHub account upon publication: (https://github.com/Lerm-Lab/COPE_epigenetics/).