The Trophoblast Surface Becomes Refractory to Adhesion by Congenitally Transmitted and During Cytotrophoblast to Syncytiotrophoblast Development

The placenta is a critical barrier against viral, bacterial, and eukaryotic pathogens. For most teratogenic pathogens, the precise molecular mechanisms of placental resistance are still being unraveled. Given the importance of understanding these mechanisms and challenges in replicating trophoblast-pathogen interactions using models, we tested an existing stem-cell-derived model of trophoblast development for its relevance to infection with . We grew human trophoblast stem cells (TS) under conditions leading to either syncytiotrophoblast (TS) or cytotrophoblast (TS) and infected them with . We evaluated proliferation and invasion, cell ultrastructure, as well as for transcriptome changes after infection. TS cells showed similar ultrastructure compared to primary cells and villous explants when analyzed by transmission electron microscopy and scanning electron microscopy (SEM), a resistance to adhesion could be visualized on the SEM level. Furthermore, TS were highly refractory to parasite adhesion and replication, while TS were not. RNA-seq data on mock-treated and infected cells identified differences between cell types as well as how they responded to infection. We also evaluated if TS-derived SYNs and CYTs had distinct resistance profiles to another vertically transmitted facultative intracellular pathogen, . We demonstrate that TS are highly resistant to , while TS are not. Like , TS resistance to was at the level of bacterial adhesion. Altogether, our data indicate that stem-cell-derived trophoblasts recapitulate resistance profiles of primary cells to and highlight the critical importance of the placental surface in cell-autonomous resistance to teratogens.IMPORTANCECongenital toxoplasmosis can cause a devastating consequence to the fetus. To reach the fetus's tissues, must cross the placenta barrier. However, how this parasite crosses the placenta and the precise molecular mechanisms of placental resistance to this parasite are still unknown. In this study, we aimed to characterize a new cellular model of human trophoblast stem cells to determine their resistance, susceptibility, and response to . Syncytiotrophoblast derived from trophoblast stem cells recapitulate the resistance profile similarly to placenta cells. We also showed that these cells are highly resistant to , at the level of bacterial adhesion. Our results suggest that resisting pathogen adhesion/attachment may be a generalized mechanism of syncytiotrophoblast resistance, and trophoblast stem cells represent a promising model to investigate cell-intrinsic mechanisms of resistance to pathogen adhesion and replication.