The imbalance of TNF and IL-6 levels and FOXP3 expression at the maternal-fetal interface is involved in adverse pregnancy outcomes in a susceptible murine model of congenital toxoplasmosis

Abstract

Vertical transmission of Toxoplasma gondii leads to adverse pregnancy outcomes depending on the time at which the infection occurs and the immunological state of the mother. C57BL/6 and BALB/c mice have been described as susceptible and resistant mouse lineages to congenital T. gondii infection, respectively. This study aimed to elucidate the systemic and local cytokine profile of pregnant mice infected with T. gondii and whether the expression of the transcription factor FOXP3, related to T regulatory cells, is associated with the resistance/susceptibility of these lineages of mice in the context of experimental congenital toxoplasmosis. For this purpose, C57BL/6 and BALB/c females were orally infected with the T. gondii ME-49 strain on the day of vaginal plug detection or day 14 of gestation, examined 7 or 5 days later, respectively, as models of early and late pregnancy. Cytokine levels were measured systemically and in the uterus/placenta. Additionally, the uterus/placenta were evaluated macroscopically for resorption rates and histologically for parasite and FOXP3 immunostaining. The FOXP3 protein expression was also evaluated by western blotting assay. It was found that, during early pregnancy, the infection leads to high IFN-γ, TNF and IL-6 levels systemically, with the TNF levels being higher in C57BL/6 mice. At the maternal-fetal interface, the infection induced high levels of IFN-γ in both mouse lineages; however, higher levels were observed in BALB/c, while high TNF and IL-6 levels were found in C57BL/6, but not in BALB/c mice. In contrast, in late gestation, T. gondii interfered less strongly with the cytokine profile. In early pregnancy, a reduction of FOXP3 expression at the maternal-fetal interface of infected mice was also observed, and the reduction was larger in C57BL/6 compared with BALB/c mice. Additionally, the parasite was seldom found in the uterus/placenta. Thus, the worse pregnancy outcomes observed in C57BL/6 mice were associated with higher TNF systemically, and TNF and IL-6 at the maternal-fetal interface, with lower FOXP3 expression.