Abstract
Toxoplasma gondii infection evokes a strong Th1-type response with interleukin (IL)-12 and interferon (IFN)-γ secretion. Recent studies suggest that the infection of pregnant mice with T. gondii may lead to adverse pregnancy results caused by subversion of physiological immune tolerance at maternofetal interface rather than direct invasion of the parasite. Genotype-associated dense granule protein GRA15II tends to induce classically activated macrophage (M1) differentiation and subsequently activating NK, Th1, and Th17 cells whereas rhoptry protein ROP16I/III drives macrophages to alternatively activated macrophage (M2) polarization and elicits Th2 immune response. Unlike the archetypal strains of types I, II, and III, type Chinese 1 strains possess both GRA15II and ROP16I/III, suggesting a distinct pathogenesis of Toxoplasma-involved adverse pregnancies. We constructed T. gondii type Chinese 1 strain of WH3Δrop16 based on CRISPR/Cas9 technology to explore the ROP16I/III-deficient/GRA15II-dominant parasites in induction of trophoblast apoptosis in vitro and abnormal pregnant outcomes of mice in vivo. Our study showed that Toxoplasma WH3Δrop16 remarkably induced apoptosis of trophoblasts. C57BL/6 pregnant mice injected with the tachyzoites of WH3Δrop16 presented increased absorptivity of fetuses in comparison with the mice infected with WH3 wild type (WH3 WT) parasites although no remarkable difference of virulence to mice was seen between the two strains. Additionally, the mice inoculated with WH3Δrop16 tachyzoites exhibited a notable expression of both IL-17A and IFN-γ, while the percentage of CD4+CD25+FoxP3 [T regulatory cells (Tregs)] were diminished in splenocytes and placenta tissues compared to those infected with WH3 WT parasites. Accordingly, expressions of IL-4, IL-10, and transforming growth factor beta 1, the pivotal cytokines of Th2 and Tregs response, were significantly dampened whereas IFN-γ and IL-12 expressions were upregulated in WH3Δrop16-infected mice, which gave rise to more prominent outcomes of abnormal pregnancies. Our results indicated that the WH3Δrop16 parasites with gra15II background of T. gondii type Chinese 1 strains may cause miscarriage and stillbirth due to subversion of the maternal immune tolerance and system immunity of the animals and the GRA15II effector contributes to the process of adverse pregnant consequences.
Highlights
During normal pregnancy, allogeneic fetal cells invading the extraembryonic trophoblasts do not impair gestation by establishing tolerance at the maternal–fetal interface [1, 2]
We explored the impact of GRA15II with ROP16I/III deletion of Chinese 1 WH3 strain parasite on adverse pregnancy outcomes in murine model by making a T. gondii WH3Δrop16 strain based on CRISPR/Cas9 technology
Virulence examination indicated that all animals infected by both strains died on day 12 post-infection (Figure 1E) and no difference of the virulence to mice was noted between WH3 wild type (WH3 WT) and WH3Δrop16 strains
Summary
Allogeneic fetal cells invading the extraembryonic trophoblasts do not impair gestation by establishing tolerance at the maternal–fetal interface [1, 2]. Previous studies showed that apoptosis is a normal physiological process of trophoblasts throughout gestation and is essential to normal placental development and fetal growth [4]. Any unfavorable impact of immunological factors on the maternal–fetal interface and/or apoptosis of trophoblasts may lead to abnormal pregnancy outcomes. It has been elucidated that T regulatory cells (Tregs) promote immune tolerance and successful pregnancy by secreting interleukin (IL)-10 and transforming growth factor beta 1 (TGF-β1) and dampen interferon (IFN)-γ and other inflammatory cyto kines to maintain the normal development of embryos [5,6,7,8]. Th2-dominant response in system immunity and at maternal–fetal interface is the prerequisite for normal pregnancy [3, 11,12,13,14]
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