Project summary/abstract: Infection-induced developmental divergence in the transplacental transmission strategy of Toxoplasma gondii. Toxoplasma gondii is the world’s most ubiquitous human parasitic infection. Infection of pregnant women can result in transmission of the parasite to the developing fetus, often causing devastating birth defects. Fetal infection requires the parasite to cross the maternal-fetal barrier, a junction primarily defended by the placenta. The strategy by which T. gondii surmounts this tissue barrier is poorly understood at both the cellular and molecular level. Critical to this process are placental trophoblasts, cells that undergo coordinated development into distinct differentiated subtypes (most notably progenitor cytotrophoblasts, CYTs; syncytiotrophoblasts, SYNs; and extravillous trophoblasts; EVTs) to form the maternofetal interface, and which previous data show are differentially susceptible to T. gondii infection. The proposed studies test the hypothesis that T. gondii infection of CYTs alters their developmental trajectory to promote parasite infection in a manner that disrupts proper placental and fetal development. This hypothesis was formulated based on preliminary transcriptome and immunofluorescence data showing that T. gondii-infected CYTs bear gene expression signatures that are more similar to infection-permissive EVTs compared to infection-resistant SYNs. These data suggest that T. gondii- infection alters cell fate to favor one lineage at the cost of the other, possibly to its own advantage. In the proposed studies I will use a bipotent in vitro trophoblast stem cell system and organoid model of placental development to investigate 1) the extent of T. gondii-driven disruption of placental trophoblast development and 2) how this impacts placental trophoblast function.

Project Narrative: Toxoplasma gondii infects a third of the global population and, when contracted by a pregnant woman, can cause severe disease in the developing fetus. In order to reach the fetus, T. gondii must surmount the placenta, an organ that has evolved specifically to restrict pathogens. This proposal investigates how T. gondii manipulates the development and function of placental cells to facilitate its own transmission.