Whole transcriptome profiling of placental pathobiology in SARS-CoV-2 pregnancies identifies placental dysfunction signatures

ABSTRACT Objectives Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a “preeclampsia-like syndrome”. However, the mechanisms underpinning SARS-CoV-2-induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS-CoV-2 infection. Methods We utilized whole-transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS-CoV-2 in the third trimester of their pregnancy (n=7) and those collected prior to the start of the coronavirus disease 2019 (COVID-19) pandemic (n=9). Results Through comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified signatures associated with hypoxia and placental dysfunction during SARS-CoV-2 infection in pregnancy. Notably, genes associated with vasodilation ( NOS3 ), oxidative stress ( GDF15 , CRH ), and preeclampsia ( FLT1, EGFR, KISS1, PAPPA2), were enriched with SARS-CoV-2. Pathways related to increased nutrient uptake, vascular tension, hypertension, and inflammation, were also enriched in SARS-CoV-2 samples compared to uninfected controls. Conclusions Our findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS-CoV-2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS-CoV-2 infection. Graphical abstract In this study, using spatial digital profiling transcriptomic approaches, we demonstrate that SARS-CoV-2 infection in pregnancy disrupts optimal placental function by altering the genomic architecture of trophoblasts and villous core stromal cells.