Dataset Information

Toxoplasma gondii ROP16I Deletion: The Exacerbated Impact on Adverse Pregnant Outcomes in Mice.

ABSTRACT: Imbalance of Th1 and Th2 response at the maternal-fetal interface is considered as a radical event in the pathogenesis of immunity-related pregnant diseases. It has been demonstrated that the ROP16I, a rhoptry protein of Toxoplasma gondii, and the viable parasite with ROP16I may induce M2 macrophage polarization in host innate immunity and may be involved in the adverse pregnant outcomes. However, the mechanisms by which T. gondii-derived effectors subvert the immune tolerance in the pathology of pregnancy remain unclear. Here, we constructed the RH strain with ROP16I deletion (RH?rop16) to explore the pathogenesis of abnormal pregnancy. We found that C57BL/6 mice infected with RH?rop16 exhibited the increased resorption of fetuses and more severe adverse pathology of placentae at the early phase of gestation, as compared to the mice infected with RH wild type (RH WT) parasite. Additionally, RH?rop16 strain infection significantly promoted M1 macrophage phenotypes of CD80 and CD86, and decreased CD206 expression of M2 macrophages, with upregulation of the iNOS and downregulation of the Arg-1 expression in placental homogenates. Simultaneously, the pro-inflammatory cytokines of IL-12 and TNF-? were elevated whereas the anti-inflammatory cytokine of TGF-?1 was dampened. Moreover, the p38? mitogen-activated protein kinase (p38? MAPK) was notably phosphorylated in placental macrophages infected with both RH?rop16 and RH WT strains compared with the control. Taken together, our findings indicated that ROP16I deletion of type I RH strain may cause exacerbated adverse pregnant outcomes, which is attributable to subversion of the maternal immune tolerance due to the increased pro-inflammatory cytokines in the pregnant animals. The results also suggest that ROP16I might be a protective factor and other T. gondii-derived molecules might be involved in the M1-Th1 biased pathological process in aberrant pregnancy at the early phase of gestation.

SUBMITTER: Cui W

PROVIDER: S-EPMC7005636 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Toxoplasma gondii ROP16I Deletion: The Exacerbated Impact on Adverse Pregnant Outcomes in Mice.

Cui Wen W Wang Cong C Luo Qingli Q Xing Tian T Shen Jilong J Wang Wei W

Frontiers in microbiology 20200131

Imbalance of Th1 and Th2 response at the maternal-fetal interface is considered as a radical event in the pathogenesis of immunity-related pregnant diseases. It has been demonstrated that the ROP16I, a rhoptry protein of Toxoplasma gondii, and the viable parasite with ROP16I may induce M2 macrophage polarization in host innate immunity and may be involved in the adverse pregnant outcomes. However, the mechanisms by which T. gondii-derived effectors subvert the ...[more]

PMID: 32082272

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Project description:ObjectiveQuantified risks of congenital Toxoplasma gondii infection and abnormal pregnancy outcomes following primary maternal infection were evaluated with meta- analysis based on published studies.MethodsThe related literatures were searched in multiple literature databases regardless of languages. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the risks of vertical transmission of Toxoplasma gondii and abnormal pregnancy outcomes following primary maternal infection with meta-analysis.Results53 of the 2632 searched literatures were included in our analysis. The incidence of abnormal pregnancy outcomes in T. gondii infected pregnant women (infected group) was significantly higher than that in the uninfected pregnant women (control group) (OR = 5.10; 95% CI, 3.85-6.75). Toxoplasma gondii infection rate in the abnormal-pregnancy-outcome group was significantly higher than in the normal-pregnancy group (OR = 3.71; 95% CI, 3.31-4.15). The pooled rate of vertical transmission was 20% (95% CI, 15%-26%) in maternal infection of T. gondii. The incidences of vertical transmission in women who were infected in the first, second or third trimester of pregnancy were 5% (95%CI, 2%-16%), 13% (95%CI, 7%-23%), and 32% (95%CI, 24%-41%), respectively. The rates of vertical transmission in women who were treated with spiramycin-only, PSF (pyrimethamine + sulfadiazine + folinic acid) or PS (pyrimethamine + sulfadiazine) combined with spiramycin, or other untypical treatments were 13% (95%CI, 7%-22%), 13%(95%CI, 7%-25%), and 24%(95%CI, 18%-32%), respectively.ConclusionsToxoplasma gondii infection can result in adverse pregnancy outcomes in pregnant women. The pooled rate of vertical transmission was 20% in maternal infection and the incidences of vertical transmission increased in the first, second or third trimester of pregnancy. The pooled rates of transmission in groups treated with spiramycin-only, PSF or PS combined with spiramycin, or other untypical treatments were not significantly different.

Project description:Background:Toxoplasma gondii (T. gondii) is an obligate intracellular parasite, which can affect the pregnancy outcomes in infected females by damaging the uterus, and the intrauterine environment as well as and the hypothalamus resulting in hormonal imbalance. However, the molecular mechanisms underlying the parasite-induced poor pregnancy outcomes and the key genes regulating these mechanisms remain unclear. Therefore, this study aimed to analyze the gene expression in the mouse's uterus following experimentally-induced acute infection with T. gondii RH strain. Three groups of female mice were intraperitoneally injected with tachyzoites as follow; 3 days before pregnancy (FBD6), after pregnancy (FAD6), and after implantation (FID8) as the experimental groups. Another corresponding three groups served as control, were injected with normal saline at the same time. Transcriptome analysis of the total RNA extracted from both infected and non-infected mouse uterus samples was performed using RNA sequencing (RNA-Seq). Results:The three experimental groups (FBD6, FAD6, and FID8) had a total of 4,561, 2,345, and 2,997 differentially expressed genes (DEGs) compared to the controls. The significantly upregulated and downregulated DEGs were 2,571 and 1,990 genes in FBD6, 1,042 and 1,303 genes in FAD6 and 1,162 and 1,835 genes in FID8 group, respectively. The analysis of GO annotation, and KEGG pathway showed that DEGs were mainly involved in anatomical structure development, transport, cell differentiation, embryo development, hormone biosynthetic process, signal transduction, immune system process, phagosome, pathways in cancer, and cytokine-cytokine receptor interaction pathways. Conclusion:T. gondii infection can induce global transcriptomic changes in the uterus that may cause pregnancy hypertension, destruct the intrauterine environment, and hinder the normal development of placenta and embryo. Our results may help to understand the molecular mechanisms of the acute T. gondii infection, which could promote the development of new therapeutics or prophylactics for toxoplasmosis in pregnancy.

Project description:Toxoplasma gondii is a common protozoan parasite that infects warm-blooded animals throughout the world, including mice and humans. During infection, both, the parasite and the host, utilize various mechanisms to maximize their own reproductive success. Mice and humans are both the intermediate hosts for Toxoplasma gondii, which forms specialized vacuoles containing reproductive cysts in the formers' tissue. As half of the human population is infected, developing a disease called toxoplasmosis, along with an ever-growing number of couples suffering with idiopathic infertility, it is therefore surprising that there is a lack of research on how Toxoplasma gondii can alter reproductive parameters. In this study, a detailed histometric screening of the testicular function along with the levels of the pituitary luteinizing hormone (LH) were analysed in infected mice. Data on relative testis and epididymis weight, and sperm count were also collected. Based on the results obtained, the level of LH in the urine of Toxoplasma gondii infected mice was lower compared to the control. In direct correlation with the hormone level, testicular function and sperm production was also significantly lower in Toxoplasma gondii positive group using sperm count and histometric analysis as a marker. Not only were the number of leptotene primary spermatocytes and spermatids lowered, but the number of Sertoli cells and the tubule diameter were elevated. In parallel, a pilot epigenetic study on global testicular methylation, and specific methylation of Crem, Creb1 and Hspa1genes essential for successfully ongoing spermatogenesis was performed. Global methylation was elevated in Toxoplasma infected mice, and differences in the DNA methylation of selected genes were detected between the Toxoplasma positive and control group. These findings demonstrate a direct relation between Toxoplasma gondii infection and the decrease of male reproductive fitness in mice, which may contribute to an increase of idiopathic infertility in humans.

Dataset Information

Toxoplasma gondii ROP16I Deletion: The Exacerbated Impact on Adverse Pregnant Outcomes in Mice.

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<i>Toxoplasma gondii</i> ROP16<sub>I</sub> Deletion: The Exacerbated Impact on Adverse Pregnant Outcomes in Mice.

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