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  • Title: [Expression of CD47 and its ligands in pregnant mice infected with Toxoplasma gondii during pregnancy].
    Author: Bi X, Fu X, Xue S, Han X, Zeng Y, Sun J, Liu D.
    Journal: Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi; 2023 Mar 13; 35(1):51-62. PubMed ID: 36974015.
    Abstract:
    OBJECTIVE: To investigate the dynamic expression of cluster of differentiation 47 (CD47) and its ligands signaling regulatory protein α (SIRPα) and thrombospondin-1 (TSP-1) in mice infected with Toxoplasma gondii in the second and third trimesters. METHODS: C57BL/6J mice (6 to 8 weeks old) were used for modeling T. gondii infection in the first trimester, and the pregnant mice were randomly divided into the normal control and infection groups, of 10 mice in each group. Pregnant mice in the infection group were intraperitoneally injected with 150 T. gondii tachyzoites on gestational day (Gd) 6.5, while pregnant mice in the normal control group were intraperitoneally injected with the same volume of physiological saline at the same time. The uterine and placental specimens were collected from all pregnant mice on Gd12.5 and Gd18.5, and the pregnant outcomes were recorded. The pathological damages of mouse uterine and placental specimens were observed using hematoxylin-eosin (HE) staining on Gd12.5 and Gd18.5. The relative expression of CD47, SIRPα, TSP-1, surface antigen 1 (SAG1), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-13 mRNA was quantified in mouse uterine and placental specimens using real-time fluorescence quantitative PCR (qPCR) assay, and the CD47, SIRPα, TSP-1 expression was determined in mouse uterine and placental specimens using immunohistochemical staining. RESULTS: As compared with those in the normal control group, the pregnant mice in the infection group showed back arching, bristling, trembling and listlessness during pregnancy, and several mice presented virginal bleeding and abortion. Pathological examinations showed inflammatory cell infiltration, congestion and necrosis in uterine and placental specimens of pregnant mice in the infection group, a higher abortion rate of pregnant mice was seen in the infection group than in the normal control group on Gd12.5 (χ2 = 20.405, P < 0.001) and Gd18.5 (χ2 = 28.644, P < 0.001). qPCR assay showed significant differences in the expression of CD47, SIRPα, TSP-1, SAG1, INF-γ, IL-2, IL-4 and IL-13 genes in mouse placental specimens between the normal control and infection groups on Gd12.5 and Gd18.5 [F' (F) = 37.511, 29.337, 97.343, 53.755, 67.188, 21.145, 8.658 and 13.930, all P values < 0.001]. Higher CD47, SIRPα and TSP-1 gene expression was quantified in mouse placental specimens in the infection group than in the normal control group on Gd12.5 (all P values < 0.01), and lower CD47, SIRPα and TSP-1 gene expression was quantified in the infection group than in the normal control group on Gd18.5 (all P values < 0.001), while higher SAG1 gene expression was detected in placental specimens of pregnant mice in the infection group than in the normal control group on Gd12.5 and Gd18.5 (both P values < 0.01). In addition, higher INF-γ and IL-2 expression and lower IL-4 and IL-13 expression was detected in mouse placental specimens in the infection group than in the normal control group on Gd12.5 and Gd18.5 (all P values < 0.001), and there were significant differences in the CD47, SIRPα, TSP-1, SAG1, INF-γ, IL-2, IL-4 and IL-13 gene expression in uterine specimens of pregnant mice between the normal control and infection groups on Gd12.5 and Gd18.5 [H(F' and F) = 14.951, 25.977, 18.711, 48.595, 39.318, 14.248 and 15.468, all P values < 0.01], and higher CD47 and TSP-1 expression was detected in mouse uterine specimens in the infection group than in the control group on Gd12.5 and Gd18.5 (all P values < 0.01); however, no significant difference was found in the SIRPα expression (P > 0.05). Higher SAG1 expression was detected in uterine specimens of pregnant mice in the infection group than in the normal control group on Gd12.5 and Gd18.5 (both P values < 0.01), and higher INF-γ and IL-2 gene expression and lower IL-4 and IL-13 gene expression was found in the placental specimens of pregnant mice in the infection group than in the normal control group on Gd12.5 and Gd18.5 (all P values < 0.001). Spearman correlation analysis showed that the CD47 gene expression correlated positively with IFN-γ (rs = 0.735, P < 0.05) and IL-2 (rs = 0.655, P < 0.05) and negatively with IL-4 (rs = -0.689, P < 0.05) and IL-13 expression (rs = -0.795, P < 0.05) in the placental specimens of pregnant mice in the infection group on Gd12.5, and the CD47 gene expression correlated negatively with IFN-γ (rs = -0.745, P < 0.05) and IL-2 expression (rs = -0.816, P < 0.05) and positively with IL-4 (rs = 0.704, P < 0.05) and IL-13 (rs = 0.802, P < 0.05) in the placental specimens of pregnant mice in the infection group on Gd18.5. Immunohistochemical staining showed mild CD47, SIRPα and TSP-1 expression in uterine and placental specimens of pregnant mice in the normal control group on Gd12.5 and Gd18.5, strong CD47, SIRPα and TSP-1 expression in the placental specimens of pregnant mice in the infection group on Gd12.5 and strong CD47 and TSP-1 expression in the uterine specimens of pregnant mice in the infection group on Gd12.5. CONCLUSIONS: T. gondii infection in the first trimester may cause abnormal expression of CD47 and its ligands SIRPα and TSP-1 in the maternal-fetal interface of pregnant mice in the second and third trimesters, which may be associated with the immune escape of T. gondii at the maternal-fetal interface. ［摘要］ 目的 观察孕早期弓形虫感染小鼠中分化簇CD47及其配体信号调节蛋白 α (SIRPα) 和血小板反应蛋白1 (TSP-1) 在孕中、晚期的动态表达。方法 以C57BL/6J小鼠 (6~8周龄) 构建孕早期弓形虫感染小鼠模型, 将孕鼠随机分成正常 对照组和感染组, 每组10只。感染组孕鼠于孕6.5 d (Gd6.5) 时腹腔注射150个弓形虫速殖子, 正常对照组孕鼠同一时间 腹腔注射等体积生理盐水。于Gd12.5、Gd18.5时, 收集各组孕鼠子宫和胎盘组织, 并记录妊娠状态结局。通过苏木精-伊 红 (HE) 染色观察两组孕鼠子宫、胎盘组织Gd12.5和Gd18.5时病理损伤, 采用实时荧光定量PCR (qPCR) 检测各组孕鼠子 宫、胎盘组织中CD47、SIRPα 、TSP-1、主要表面抗原1 (SAG1) 及γ干扰素 (IFN-γ) 、白细胞介素2 (IL-2) 、IL-4 和IL-13 mRNA 表达水平, 采用免疫组织化学技术检测CD47、SIRPα和TSP-1在孕鼠子宫、胎盘组织中的表达水平。结果 与正常对照 组相比, 感染组孕鼠孕期出现弓背、耸毛、颤栗和精神萎靡状态, 个别出现阴道流血和流产等现象。HE染色结果显示, 感 染组孕鼠子宫、胎盘组织均出现不同程度炎症细胞浸润、淤血和坏死等病理损伤。Gd12.5和Gd18.5时, 感染组孕鼠流产 率均较对照组升高 (χ2 = 20.405、28.644, P 均< 0.001) 。qPCR检测结果显示, Gd12.5和Gd18.5时正常对照组和感染组孕 鼠胎盘组织中CD47、SIRPα、TSP-1、SAG1、INF-γ、IL-2、IL-4 和IL-13 表达水平差异均有统计学意义[F′ (F) = 37.511、29.337、97.343、53.755、67.188、21.145、8.658、13.930, P 均< 0.001]; 与对照组相比, Gd12.5 时感染组孕鼠胎盘组织中 CD47、SIRPα和TSP-1 表达水平升高 (P 均< 0.01), 而Gd18.5时表达降低 (P 均< 0.001) ; Gd12.5和Gd18.5时感染组孕鼠胎 盘组织中均有SAG1 表达 (P 均< 0.01) ; 此外, Gd12.5和Gd18.5时感染组孕鼠胎盘组织中INF-γ 和IL-2 表达水平均升高 (P 均< 0.001), IL-4和IL-13表达下降 (P 均< 0.001) 。Gd12.5和Gd18.5时正常对照组和感染组孕鼠子宫组织中CD47、TSP-1、 SAG1、INF-γ、IL-2、IL-4 和IL-13 表达水平差异均有统计学意义[H (F′、F) = 14.951、25.977、18.711、48.595、39.318、14.248、 15.468, P 均< 0.01]; 与正常对照组相比, Gd12.5和Gd18.5时感染组孕鼠子宫组织中CD47 和TSP-1 表达水平均升高 (P 均< 0.01), 但SIRPα 表达无变化 (P > 0.05) ; Gd12.5和Gd18.5时感染组孕鼠子宫组织中均有SAG1 表达 (P 均< 0.01) ; Gd12.5和Gd18.5时感染组孕鼠子宫组织中INF-γ 和IL-2 表达水平均升高 (P 均< 0.001), IL-4 和IL-13 表达水平下降 (P 均< 0.001) 。相关性分析显示, Gd12.5时感染组孕鼠胎盘组织中CD47 表达水平与IFN-γ (rs = 0.735) 、IL-2 (rs = 0.655) 表达 水平呈正相关 (P 均< 0.05), 与IL-4 (rs = −0.689) 、IL-13 表达水平 (rs = −0.795) 呈负相关 (P 均< 0.05) ; Gd18.5时胎盘组织中 CD47表达水平与IFN-γ 表达水平 (rs = −0.745) 、IL-2 (rs = −0.816) 呈负相关 (P 均< 0.05), 与IL-4 (rs = 0.704) 、IL-13 表达水平 (rs = 0.802) 呈正相关 (P 均< 0.05) 。免疫组织化学染色结果显示, Gd12.5和Gd18.5时正常对照组孕鼠子宫、胎盘组织中 CD47、SIRPα和TSP-1均呈弱表达; Gd12.5时感染组孕鼠胎盘组织中CD47、SIRPα和TSP-1呈强表达, 子宫组织中CD47 和TSP-1呈强表达。结论 孕早期弓形虫感染可致小鼠孕中、晚期母胎界面出现CD47及其配体SIRPα和TSP-1异常表 达, 可能与虫体在母胎界面免疫逃逸有关。.
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