Title: Toxoplasma gondii restricts placental trophoblast differentiation from an infection-resistant canonical lineage
Abstract:
Pregnancy is perhaps the most critical point of vulnerability to infection. As one of just a few pathogens that are able infect and harm the fetus during gestation, Toxoplasma gondii displays remarkable capacity to evade the evolved defenses of the placenta. Yet, no specific mechanisms driving the parasite’s transplacental transmission strategy have been discovered, despite a clear epidemiological directive. Here, I investigate an entirely new phenomenon where Toxoplasma is able to coopt canonical host cell development to propagate its own transmission through the placenta. In this work, I have used parallel systems of trophoblast stem cells and 3D primary trophoblast organoids to reconstruct the placental environment. With these tools, we can grow cells that recapitulate trophoblast progenitors, called cytotrophoblasts (CYT), in addition to both differentiated subtypes, extravillous trophoblasts (EVT) and syncytiotrophoblasts (SYN). These cells vary in their susceptibility to T. gondii infection, with SYN being unusually resistant and EVT being comparably permissive. Critically, the high proportion of infection-resistant SYN at the surface of the maternofetal interface prevents the vast majority of parasite invasion to deeper cell layers. However, T. gondii-infected TS-CYT undergo global transcriptional changes consistent with a departure from their progenitor state and activation of host cell differentiation that is antagonistic to the TS-SYN cell lineage. ScRNA-seq and Western blot reveal a simultaneous reduction of transcripts and proteins governing SYN development and increase in transcripts governing EVT development. Fusion assays have determined T. gondii-infected TS-CYT are unable to become TS-SYN, indicating a functional loss of fusogenicity that is essential for SYN replenishment. In trophoblast organoids, infection is sufficient to elicit differentiation of CYT to HLA-G(+) cells and increase MMP2 secretion, both canonical indicators of EVT development, in just 24 hours. These changes are accompanied by a massive transcriptional increase of the decidua-derived EVT differentiation factor, NRG1, specifically in T. gondii-infected cells. Collectively, these data indicate that T. gondii both initiates cell differentiation and directs it away from an infection-restrictive lineage in placental trophoblast progenitor cells. Overall, this significant shift of CYT away from SYN and towards EVT could alter the balance of resistant and susceptible cells at the maternofetal interface, potentiating robust T. gondii dissemination through placental tissue and on to fetal cells.
Boyle Lab
Friday, February 16th, 2024
12:00PM
Langley A219B