SARS-CoV-2 Delta and Omicron Variants alter Trophoblast Cell Fusion and Syncytiotrophoblast Dynamics: New Insights into Placental Vulnerability

Pregnancy constitutes an at-risk factor for severe COVID-19. Several clinical studies have previously suggested increased risks of adverse obstetrical outcomes and placental pathological changes in pregnant women infected with SARS-CoV-2. In this study, our goal was to assess the susceptibility of trophoblast to SARS-CoV-2 infection at early stage of pregnancy and its impact on trophoblast cell fusion in vitro . We showed that first trimester cytotrophoblast (CTB) and syncytiotrophoblast (STB) are permissive to SARS-CoV-2 in variant- and donor-dependent manner. Delta variant showed a higher efficiency of replication in STB and CTB compared to Omicron BA.1, BA.2 and BA.5. In STB, despite a slight subsequent increase of type III IFN response, no correlation was observed between virus replication and the induction of the overall host response (including expression of entry receptors and immune response) after infection. In CTB, virus replication significantly correlated with the increased level of trophoblast cell fusion leading to syncytia formation. In line with increased STB formation in vitro , we in vivo observed an increase of syncytial knots release in early placenta infected by SARS-CoV-2 compared both to SARS-CoV-2- negative areas from the same placenta, and to age matched references. Altogether, our in vitro and in vivo data suggested that efficient replication of SARS-CoV-2 variants in placenta cells during early stage of pregnancy might alter STB turnover.