Developmental disruption in the transplacental transmission strategy of Toxoplasma gondii

弓形虫经胎盘传播策略的发育破坏

• 批准号: 10641674
• 负责人: Leah Frances Cabo
• 金额: $ 3.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641674
• 关键词: Arteries; Automobile Driving; Biological Markers; Biology; Blood Circulation; Cell Differentiation process; Cell Line; Cell physiology; Cells; Congenital Abnormality; Congenital Toxoplasmosis; Contracts; Cytomegalovirus; Data; Development; Developmental Biology; Diffuse; Disease; Elements; Endometrium; Eye diseases; Fetal Development; Fetus; Future; Gene Expression Profile; Human; Immunofluorescence Immunologic; In Vitro; Infection; Invaded; Live Birth; Maps; Mediating; Mesenchymal; Metabolic; Modeling; Molecular; Mothers; Multipotent Stem Cells; Nervous System Trauma; Nutrient; Organ; Organoids; Oxygen; Parasites; Parasitic infection; Parasitology; Perinatal Infection; Physiology; Placenta; Placentation; Population; Predisposition; Pregnancy; Pregnant Women; Process; Proliferating; Resistance; Rubella; Signal Transduction; Syncytiotrophoblast; System; Testing; Time; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Villous; Work; ZIKA; blastomere structure; blood perfusion; cell type; congenital infection; cost; cytotrophoblast; disability; embryo cell; fetal; fetal infection; in vivo; insight; knock-down; mRNA sequencing; member; neglect; pathogen; permissiveness; progenitor; secondary infection; stem cell model; stem cells; success; transcription factor; transcriptome; transmission process; trophoblast; trophoblast stem cell; wound healing

Project summary/abstract: Infection-induced developmental divergence in the transplacental transmission strategy of Toxoplasma gondii. Toxoplasma gondii is the world’s most ubiquitous human parasitic infection. Infection of pregnant women can result in transmission of the parasite to the developing fetus, often causing devastating birth defects. Fetal infection requires the parasite to cross the maternal-fetal barrier, a junction primarily defended by the placenta. The strategy by which T. gondii surmounts this tissue barrier is poorly understood at both the cellular and molecular level. Critical to this process are placental trophoblasts, cells that undergo coordinated development into distinct differentiated subtypes (most notably progenitor cytotrophoblasts, CYTs; syncytiotrophoblasts, SYNs; and extravillous trophoblasts; EVTs) to form the maternofetal interface, and which previous data show are differentially susceptible to T. gondii infection. The proposed studies test the hypothesis that T. gondii infection of CYTs alters their developmental trajectory to promote parasite infection in a manner that disrupts proper placental and fetal development. This hypothesis was formulated based on preliminary transcriptome and immunofluorescence data showing that T. gondii-infected CYTs bear gene expression signatures that are more similar to infection-permissive EVTs compared to infection-resistant SYNs. These data suggest that T. gondii- infection alters cell fate to favor one lineage at the cost of the other, possibly to its own advantage. In the proposed studies I will use a bipotent in vitro trophoblast stem cell system and organoid model of placental development to investigate 1) the extent of T. gondii-driven disruption of placental trophoblast development and 2) how this impacts placental trophoblast function.

项目摘要/摘要： 感染引起的发育差异在弓形虫的移植传播策略中 贡迪。弓形虫弓形虫是世界上最普遍的人类寄生虫感染。感染孕妇 可能导致寄生虫传播到发育中的胎儿，通常会导致毁灭性的先天缺陷。胎 感染要求寄生虫越过母体屏障，这是一个主要由斑点定义的连接。 在细胞和 分子水平。这一过程至关重要 变成不同的分化亚型（最著名的是祖细胞细胞细胞，细胞them; Syncitiotiotiothophophophasts， 同步；和额外的滋养细胞； EVTS）形成Maternofetal接口，并且先前的数据显示 在贡迪感染中易受不同的敏感。拟议的研究检验了T. gondii的假设 Cyts的感染改变其发育轨迹，以破坏的方式促进寄生虫感染 适当的胎盘和胎儿发育。该假设是根据初步转录组和 免疫荧光数据表明，T. gondii感染的细胞均具有更多的基因表达特征 与抗感染的同步相比，类似于感染 - 允许的EVT。这些数据表明T. gondii- 感染会改变细胞命运，以一个谱系为代价，以另一个谱系为代价。在 拟议的研究我将使用双能在体外滋养细胞干细胞系统和斑点的器官模型 开发研究1）gondii驱动的t. 2）这如何影响斑点滋养细胞功能。

项目成果

Human trophoblast stem cells can be used to model placental susceptibility to Toxoplasma gondii and highlight the critical importance of the trophoblast cell surface in pathogen resistance.

人滋养层干细胞可用于模拟胎盘对弓形虫的易感性，并强调滋养层细胞表面在病原体抵抗中的至关重要性。

• DOI: 10.1101/2023.11.10.566663
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: daSilva,RafaelaJ;Cabo,LeahF;George,JadaL;Cahoon,LatyA;Yang,Liheng;Coyne,CarolynB;Boyle,JonP
• 通讯作者: Boyle,JonP