Toxoplasma Parasite Disrupts a Protective Macrophage Signal in Pregnancy

Toxoplasma gondii infection during pregnancy is associated with placental injury and adverse pregnancy outcomes, and immune imbalance at the maternal–fetal interface is thought to play an important role in this process. A new open-access study in Parasites & Vectors, published online as a peer-reviewed accepted manuscript, reports that a signaling pathway involving the protein Trem2 in macrophages appears to act as a protective mechanism at this interface — and that the parasite disrupts it.

Macrophages are essential myeloid cells that contribute to local immune homeostasis and tissue protection during pregnancy. Trem2, a receptor previously implicated in regulating macrophage function under inflammatory or stress conditions, had not been clearly defined in the context of T. gondii-associated pregnancy complications. The research team, led by Xinyue Wang, Changyuan Ding and colleagues with Jinling Chen, set out to determine whether Trem2 and its downstream partners are affected by the parasite.

The study combined computational and laboratory approaches. Molecular docking and endogenous co-immunoprecipitation were used to investigate whether Trem2 associates with PLCγ2, an enzyme that links surface receptors to intracellular calcium signaling. The researchers then established a pregnant mouse model of T. gondii infection using both wild-type and Trem2-deficient (Trem2−/−) mice, assessing pregnancy outcomes, placental pathology, and changes in Trem2, PLCγ2 and intracellular Ca2+ signaling. In parallel, RAW264.7 macrophage-like cells and primary bone marrow-derived macrophages were stimulated with T. gondii antigens in vitro to examine the same signaling axis.

The results showed that Trem2 does associate with PLCγ2, and that this association is weakened following T. gondii-related stimulation. Mutating key residues within the predicted binding interface markedly impaired the Trem2–PLCγ2 association, supporting the specificity of the interaction. In infected pregnant mice, T. gondii infection led to fetal growth restriction and placental injury, accompanied by reduced Trem2 and PLCγ2 expression and attenuated Ca2+ signaling in placental tissues. These pathological and signaling alterations were more evident in Trem2-deficient mice, suggesting that loss of Trem2 exacerbates the damage.

The in vitro experiments were consistent with the animal findings: T. gondii antigens suppressed the Trem2–PLCγ2–Ca2+ axis in both RAW264.7 cells and primary bone marrow-derived macrophages, and the inhibitory effect was stronger under Trem2-deficient conditions. Together, the data indicate that the parasite reduces Trem2 expression, weakens the coupling between Trem2 and PLCγ2, and impairs downstream calcium signaling in macrophages.

The authors conclude that T. gondii infection disrupts a Trem2-dependent protective signaling program in macrophages, and that the Trem2–PLCγ2–Ca2+ axis may represent an important regulatory pathway involved in maternal–fetal immune homeostasis and placental protection during T. gondii-associated adverse pregnancy. Because the findings derive from mouse models and cultured macrophages exposed to parasite antigens, they establish a mechanistic association in these experimental systems rather than direct evidence in humans, and further work would be needed to determine whether the same pathway operates in human pregnancy and whether it can be therapeutically targeted.

Subject of Research: How Toxoplasma gondii infection disrupts Trem2–PLCγ2–Ca2+ signaling in macrophages at the maternal–fetal interface

Article Title: Trem2–PLCγ2–Ca2+ signaling axis in macrophages: a protective mechanism disrupted by Toxoplasma gondii infection at the maternal–fetal interface

Article References: Wang, X., Ding, C., Fu, C., Zhang, X., Cao, L., Zhu, D., & Chen, J. (2026). Trem2–PLCγ2–Ca2+ signaling axis in macrophages: a protective mechanism disrupted by Toxoplasma gondii infection at the maternal–fetal interface. Parasites & Vectors. https://doi.org/10.1186/s13071-026-07755-w

Image Credits: AI Generated

DOI: 10.1186/s13071-026-07755-w

Keywords: Toxoplasma gondii, Trem2, PLCγ2, calcium signaling, macrophages, maternal–fetal interface, placental injury, fetal growth restriction, pregnancy, immunology, Parasites & Vectors, signaling