Toxoplasma gondii infection reduces CD59 expression through downregulation of JAK2/STAT3 signaling axis to enhance decidual NK cell cytotoxicity via the RAS/MAPK pathway.

Abstract

Objective and design: Toxoplasma gondii (T. gondii) infection disrupts pregnancy by modulating decidual natural killer (dNK) cells function. This study investigates how T. gondii regulates CD59 expression in dNK cells and its impact on pregnancy outcomes.

Material or subjects: T. gondii-infected wild-type (WT) C57BL/6 and cd59a^-/- pregnant mice, as well as human primary dNK cells, were used.

Treatment: The pregnant mice were challenged intraperitoneally with T. gondii tachyzoites. Decidual immune cells and dNK cells were also infected with T. gondii in vitro.

Methods: Adverse outcomes were observed after T. gondii infection. Protein expression and transcriptional activity were evaluated using flow cytometry, Western blot, chromatin immunoprecipitation (ChIP)-PCR and dual-luciferase reporter assays. dNK cytotoxicity was measured by lactate dehydrogenase (LDH) release.

Results: T. gondii downregulated CD59 expression both in vivo and in vitro. In dNK cells, T. gondii suppressed the JAK2/STAT3 pathway, reducing p-STAT3 binding to the cd59 promoter. CD59 downregulation subsequently activated the Ras/MAPK pathway, leading to elevated IFN-γ and perforin production and enhanced cytotoxicity. Lack of cd59a exacerbated adverse pregnancy outcomes caused by T. gondii infection.

Conclusions: T. gondii suppresses CD59 in dNK cells via JAK2/STAT3 inhibition, which enhances dNK cell cytotoxicity through Ras/MAPK activation, contributing to poor pregnancy outcomes.