Toxoplasma gondii infection misdirects placental trophoblast lineage specification

Pregnancy is a critical point of vulnerability to pathogen infection. The placenta is a protective and nutrient-permeable barrier to most infectious agents, but a few can bypass its defenses. Little is known about how exposure to these pathogens impacts ongoing placental development. We demonstrate that Toxoplasma gondii misdirects the developmental program of trophoblast stem cells. Infection of progenitor cytotrophoblasts prevents fusion and differentiation to syncytiotrophoblast. Rather, T. gondii elicits a unique transcriptional identity that polarizes cytotrophoblasts toward the extravillous trophoblast fate. Strong evidence of developmental disruption is found in orthogonal models, including trophoblast stem cells, trophoblast organoids, and chorionic villi. Manipulation of cell fate by the parasite is most dramatic in trophoblast organoids, where we see outgrowth of human leukocyte antigen G (HLA-G)-positive extravillous trophoblasts. Collectively, these data show that Toxoplasma antagonizes differentiation of an infection-resistant cell type by inducing formation of an infection-permissive cell type, therefore potentiating its own fetal transmission.