Toxoplasma gondii TgMIF mediates the transmigration of extracellular parasites across the human placental barrier.

Abstract

The placenta is a critical biological barrier responsible for the healthy development of the fetus throughout pregnancy. However, the eukaryotic intracellular parasite Toxoplasma gondii (T. gondii) can cross the placental barrier by several mechanisms, including transmigration. Each year, approximately 190,000 infants are born worldwide with congenital infections caused by T. gondii, which can result in severe health complications or even death. Unfortunately, the molecular mechanisms underlying these tragic outcomes remain largely unclear, hindering the development of effective preventative strategies. To address this knowledge gap, we have developed a human in vitro placental barrier using trophoblast stem cells to study the transmigration of extracellular parasites across cellular tight junctions. Using this in vitro system, we found that T. gondii macrophage migration inhibitory factor (TgMIF), a homolog of the human cytokine MIF, mediates extracellular parasite transmigration across the cellular tight junctions. Notably, TgMIF, despite lacking a signal peptide, is actively excreted by the extracellular parasites. We found that the TgMIF expression varies across T. gondii strains and positively correlates with the strains transmigration capacity. Mechanistically, TgMIF distinctly induces the phosphorylation of extracellular signal-regulated kinase 1/2 and the dephosphorylation of focal adhesion kinase. These cellular modifications increase tight junction permeability, enhance parasite localization at these junctions, and facilitate subsequent transmigration. Furthermore, TgMIF mediates transmigration independently of the host MIF receptor CD74, indicating the involvement of alternative receptors. Thus, our findings highlight TgMIF as a critical effector that could mediate fetal infection in pregnant women via T. gondii transmigration across the placental barrier.