Completed Research

SARS-CoV-2 infection during pregnancy is associated with increased incidences of adverse pregnancy outcomes, including preterm birth, stillbirth, and preeclampsia. Direct placental infection is rarely observed, which suggests that pregnancy complications associated with COVID-19 are likely the result of the maternal inflammatory response. The maternal-fetal interface plays a vital role in achieving a successful pregnancy and is frequently disrupted in pregnancy complications. Therefore, elucidating the molecular pathways impacted by SARS-CoV-2 infection at the maternal-fetal interface is imperative for understanding the pathogenesis of COVID-19-related adverse pregnancy outcomes. In this study, we generated in-depth profiles, at both bulk and single-nuclei resolutions, of the transcriptomes and epigenomes of the maternal-fetal interface from COVID-19 patients and control donors. We discovered that SARS-CoV-2 infection in late pregnancy induced activation in immune cells via upregulation of interferon-inducible genes. Concomitantly, the angiogenesis pathway was dysregulated in endothelial cells and fibroblasts. These changes in gene expression were accompanied by concordant alterations to the chromatin states at corresponding cis-regulatory elements. Notably, retrotransposons were dysregulated in specific cell types, with elements serving as enhancers for endogenous genes. In particular, reduced activities of LTR8B elements were functionally linked to the downregulation of Pregnancy-Specific Glycoprotein (PSG) genes and other pregnancy-related genes in syncytiotrophoblasts in the COVID-19 samples. Taken together, we demonstrate the involvement of non-coding sequences in the dysregulation of immunomodulation and angiogenesis at the maternal-fetal interface of pregnancies affected by SARS-CoV-2.