A recent local study published in Nature Cell Biology has revealed transcriptomic and epigenomic dysregulation on the maternal-fetal interface (MFI) caused by maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.¹ Jointly conducted by the Department of Obstetrics and Gynecology at the Chinese University of Hong Kong (CUHK) and the Division of Life Science at the Hong Kong University of Science and Technology (HKUST), this research was first of its kind in assessing epigenetic alterations for coronavirus disease 2019 (COVID-19)-associated pregnancy.¹  

As the COVID-19 pandemic approached in waves, increasing numbers of pregnant patients infected with SAR-CoV-2 were hospitalized.^1,2 These patients experienced more severe disease progressions, with about a 3-fold increase in the risk of intensive care unit (ICU) admission and requiring invasive ventilation, a 2.4-fold increase in the need for extracorporeal membrane oxygenation (ECMO), as well as a 1.7-fold increase in death from the infection compared to non-pregnant patients.³ In general, the risk of preeclampsia, pre-term birth and stillbirth would be increased with infection during pregnancy, especially in those with third-trimester infections.^1,4 However, vertical viral transmission was reportedly rare, suggesting that an alternative mechanism was culpable for placental damage.¹

In this case-controlled study, 7 pregnant patients who tested positive for SARS-CoV-2 with a cycle threshold (Ct) ≤35 using quantitative polymerase chain reaction with reverse transcription (RT-qPCR) of deep throat saliva or nasopharyngeal swabs, and 7 uninfected women were enrolled.¹ Tissue samples were collected from midway between the umbilical cord insertion site and placental disk edge within 2 hours after delivery.¹ These MFI samples were subsequently frozen, pulverized, and extracted for RT-qPCR and generation of bulk ribonucleic acid-sequencing (RNA-seq) libraries.¹ Part of pulverized samples were also isolated for single-nucleus RNA-seq (snRNA-seq), single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq), bulk ATAC-seq and cleavage under targets and tagmentation (CUT&Tag) targeting acetylation and tri-methylation of histone H3 lysine 27 (H3K27ac and H3K27me3) on bulk patients.¹ For bioinformatics analysis, algorithms commonly involved sequence alignment to Genome Reference Consortium human build 38 (GRCh38/hg38) assembly using STAR, Bowtie2, Cell Ranger or Juicer algorithm.¹

Consistent with previous findings, MFI samples were tested negative for SARS-CoV-2 transcript, with negligible angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2) expression, indicating that placenta was not infected.¹ Despite that, bulk RNA-seq analysis revealed 816 differentially expressed genes (DEGs) among 21 distinct cell types.¹ Of note, genes encoding for placental development, immunomodulation and angiogenesis were impacted by maternal infection.¹

The primary target of investigation concerned pregnancy-specific glycoprotein (PSG) genes.¹ These genes were clustered on chromosome 19q13, and found to be under control of intronic LTR8B retrotransposon enhancer elements.¹ Following SARS-CoV-19 infection, LTR8B had reduced H3K27ac levels, hence reduced chromatin accessibility and weaker enhancer activity.¹ Together with reduced recruitment of GATA2 transcription factor, 7 out of 10 PSG genes were downregulated.¹ The reduction in PSG protein level might lead to impaired immunomodulation or angiogenesis and has been associated with preeclampsia or pregnancy loss.¹

For the immune system alone, most interferon-inducible (IFI) genes, especially IFI27 and IFI6, were upregulated in most placental immune cells and trophoblasts.¹ Gene ontology analysis in dendritic, Hofbauer and M2 macrophage cells further supported the involvement of interferon signaling in defense response against viruses.¹ In other words, maternal immune activation has also engaged MFI.¹

Whereas for angiogenesis, genes for receptor-ligand pair such as vascular endothelial growth factor A-fms-like tyrosine kinase-1 (VEGFA-FLT1) and fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) were upregulated.¹ Another pairing of VEGFA and endoglin (ENG) gene with their respective enhancer were also upregulated by gaining chromatin accessibility.¹ Along with activated hypoxia response genes such as nitric oxide synthase 2 (NOS2) and egl-9 family hypoxia-inducible factor 3 (EGLN3), gene ontology suggested MFI dysregulation of vasculogenesis and epithelial cell migration involving fibroblasts and vascular endothelial cells.¹

To conclude, the aggregate effect of maternal SARS-CoV-2 infection pointed towards placental harm at both epigenomic and transcriptomic levels, with inflammation, hypoxia and oxidative stress implicated.¹ To mitigate the damage, more research is needed for understanding the differential effect of SARS-CoV-2 variant infection, such that corresponding targeted therapy could be developed.¹