Toxoplasma gondii ROP18 induces maternal–fetal dysfunction by downregulating CD73 expression on decidual macrophages
Abstract Background Decidual macrophages (dMφ) are pivotal in maintaining maternal–fetal immune tolerance during normal pregnancy by expressing a range of immune-suppressive molecules, including CD73. It has been demonstrated that Toxoplasma gondii (T. gondii) infection during pregnancy can impair d...
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BMC
2025-02-01
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| Series: | Parasites & Vectors |
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| Online Access: | https://doi.org/10.1186/s13071-025-06713-2 |
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| author | Jingjing Guo Xiaohui Wang Lei Wei Shuai Li Junwei Wang Yan Zhang Ruohan Yang Han Zhang Aiqun Xu Yuzhu Jiang Xuemei Hu |
| author_facet | Jingjing Guo Xiaohui Wang Lei Wei Shuai Li Junwei Wang Yan Zhang Ruohan Yang Han Zhang Aiqun Xu Yuzhu Jiang Xuemei Hu |
| author_sort | Jingjing Guo |
| collection | DOAJ |
| description | Abstract Background Decidual macrophages (dMφ) are pivotal in maintaining maternal–fetal immune tolerance during normal pregnancy by expressing a range of immune-suppressive molecules, including CD73. It has been demonstrated that Toxoplasma gondii (T. gondii) infection during pregnancy can impair dMφ function, potentially leading to adverse pregnancy outcomes, through downregulation of these inhibitory molecules. T. gondii rhoptry protein 18 (TgROP18), a key virulence factor of T. gondii, is associated with the incapacitation of the host’s innate and adaptive immune responses to protect the parasite from elimination. However, the role of TgROP18 in modulating CD73 expression on dMφ and the underlying mechanisms remain to be elucidated. Methods Wild-type (WT) and CD73-deficient (CD73−/−) pregnant mice were subjected to intraperitoneal injection of T. gondii RH or RH-Δrop18 on gestational day (Gd) 8, and subsequently euthanized on Gd 14. Pregnancy outcomes were then evaluated, and the expression levels of CD73, arginase 1 (Arg-1), and interleukin 10 (IL-10) were quantified by flow cytometry. Mononuclear cells isolated from the human aborted decidual tissues were also infected with T. gondii RH or RH-Δrop18 for the analysis of CD73 expression with flow cytometry. Additionally, infected human dMφ were used to assess the expression levels of CD73, Arg-1, IL-10, and their associated signaling molecules by western blot analysis. Furthermore, chromatin immunoprecipitation (ChIP) assays were performed to validate the involved signaling pathways. Results Compared with the T. gondii RH-infected group, milder adverse pregnancy outcomes and attenuated expression levels of CD73 on dMφ were observed in T. gondii RH-Δrop18-infected pregnant mice and human decidual tissues. Lysine-specific histone demethylase1 (LSD1) and snail family transcriptional repressor 1 (SNAIL1) were found to be involved in the downregulation of CD73 expression on dMφ following T. gondii infection. Subsequently, reduced expression of CD73 contribute to the downregulation of Arg-1 and IL-10 expression through adenosine A2a receptor (A2AR) / protein kinase A (PKA) / phosphorylated cAMP-response element binding protein (p-CREB) / CCAAT enhancer binding protein B (C/EBPβ) pathway. Conclusions TgROP18 can significantly reduce CD73 expression on dMφ through LSD1/SNAIL1 pathway, subsequently leading to the decreased expression levels of Arg-1 and IL-10 via adenosine/A2AR/PKA/p-CREB/C/EBPβ pathway, which ultimately contributes to maternal–fetal tolerance dysfunction of dMφ. Graphical Abstract |
| format | Article |
| id | doaj-art-7ffb931263154dc1bf839ceceacf7726 |
| institution | DOAJ |
| issn | 1756-3305 |
| language | English |
| publishDate | 2025-02-01 |
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| series | Parasites & Vectors |
| spelling | doaj-art-7ffb931263154dc1bf839ceceacf77262025-08-20T02:59:28ZengBMCParasites & Vectors1756-33052025-02-0118111710.1186/s13071-025-06713-2Toxoplasma gondii ROP18 induces maternal–fetal dysfunction by downregulating CD73 expression on decidual macrophagesJingjing Guo0Xiaohui Wang1Lei Wei2Shuai Li3Junwei Wang4Yan Zhang5Ruohan Yang6Han Zhang7Aiqun Xu8Yuzhu Jiang9Xuemei Hu10Department of Gynecology and Obstetrics, Yantai Affiliated Hospital of Binzhou Medical UniversityDepartment of Immunology, Binzhou Medical UniversityCollege of Basic Medicine, Qilu Medical UniversityCollege of Basic Medicine, Qilu Medical UniversityCollege of Basic Medicine, Qilu Medical UniversityCollege of Basic Medicine, Qilu Medical UniversityDepartment of Immunology, Binzhou Medical UniversityDepartment of Immunology, Binzhou Medical UniversityDepartment of Gynecology and Obstetrics, Yantai Affiliated Hospital of Binzhou Medical UniversityDepartment of Immunology, Binzhou Medical UniversityCollege of Basic Medicine, Qilu Medical UniversityAbstract Background Decidual macrophages (dMφ) are pivotal in maintaining maternal–fetal immune tolerance during normal pregnancy by expressing a range of immune-suppressive molecules, including CD73. It has been demonstrated that Toxoplasma gondii (T. gondii) infection during pregnancy can impair dMφ function, potentially leading to adverse pregnancy outcomes, through downregulation of these inhibitory molecules. T. gondii rhoptry protein 18 (TgROP18), a key virulence factor of T. gondii, is associated with the incapacitation of the host’s innate and adaptive immune responses to protect the parasite from elimination. However, the role of TgROP18 in modulating CD73 expression on dMφ and the underlying mechanisms remain to be elucidated. Methods Wild-type (WT) and CD73-deficient (CD73−/−) pregnant mice were subjected to intraperitoneal injection of T. gondii RH or RH-Δrop18 on gestational day (Gd) 8, and subsequently euthanized on Gd 14. Pregnancy outcomes were then evaluated, and the expression levels of CD73, arginase 1 (Arg-1), and interleukin 10 (IL-10) were quantified by flow cytometry. Mononuclear cells isolated from the human aborted decidual tissues were also infected with T. gondii RH or RH-Δrop18 for the analysis of CD73 expression with flow cytometry. Additionally, infected human dMφ were used to assess the expression levels of CD73, Arg-1, IL-10, and their associated signaling molecules by western blot analysis. Furthermore, chromatin immunoprecipitation (ChIP) assays were performed to validate the involved signaling pathways. Results Compared with the T. gondii RH-infected group, milder adverse pregnancy outcomes and attenuated expression levels of CD73 on dMφ were observed in T. gondii RH-Δrop18-infected pregnant mice and human decidual tissues. Lysine-specific histone demethylase1 (LSD1) and snail family transcriptional repressor 1 (SNAIL1) were found to be involved in the downregulation of CD73 expression on dMφ following T. gondii infection. Subsequently, reduced expression of CD73 contribute to the downregulation of Arg-1 and IL-10 expression through adenosine A2a receptor (A2AR) / protein kinase A (PKA) / phosphorylated cAMP-response element binding protein (p-CREB) / CCAAT enhancer binding protein B (C/EBPβ) pathway. Conclusions TgROP18 can significantly reduce CD73 expression on dMφ through LSD1/SNAIL1 pathway, subsequently leading to the decreased expression levels of Arg-1 and IL-10 via adenosine/A2AR/PKA/p-CREB/C/EBPβ pathway, which ultimately contributes to maternal–fetal tolerance dysfunction of dMφ. Graphical Abstracthttps://doi.org/10.1186/s13071-025-06713-2Toxoplasma gondiiROP18Decidual macrophageCD73Abnormal pregnancy outcome |
| spellingShingle | Jingjing Guo Xiaohui Wang Lei Wei Shuai Li Junwei Wang Yan Zhang Ruohan Yang Han Zhang Aiqun Xu Yuzhu Jiang Xuemei Hu Toxoplasma gondii ROP18 induces maternal–fetal dysfunction by downregulating CD73 expression on decidual macrophages Parasites & Vectors Toxoplasma gondii ROP18 Decidual macrophage CD73 Abnormal pregnancy outcome |
| title | Toxoplasma gondii ROP18 induces maternal–fetal dysfunction by downregulating CD73 expression on decidual macrophages |
| title_full | Toxoplasma gondii ROP18 induces maternal–fetal dysfunction by downregulating CD73 expression on decidual macrophages |
| title_fullStr | Toxoplasma gondii ROP18 induces maternal–fetal dysfunction by downregulating CD73 expression on decidual macrophages |
| title_full_unstemmed | Toxoplasma gondii ROP18 induces maternal–fetal dysfunction by downregulating CD73 expression on decidual macrophages |
| title_short | Toxoplasma gondii ROP18 induces maternal–fetal dysfunction by downregulating CD73 expression on decidual macrophages |
| title_sort | toxoplasma gondii rop18 induces maternal fetal dysfunction by downregulating cd73 expression on decidual macrophages |
| topic | Toxoplasma gondii ROP18 Decidual macrophage CD73 Abnormal pregnancy outcome |
| url | https://doi.org/10.1186/s13071-025-06713-2 |
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