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： 弓形虫经胎盘传播策略中感染诱导的发育分化 贡地。弓形虫是世界上最普遍的人类寄生虫感染。孕妇的感染 可导致寄生虫传播给发育中的胎儿，通常会导致毁灭性的出生缺陷。胎儿 感染需要寄生虫穿过母胎屏障，这是一个主要由胎盘防御的连接。 弓形虫跨越这种组织屏障的策略在细胞和组织中都知之甚少。 分子水平。对这一过程至关重要的是胎盘滋养层细胞，即经历协调发展的细胞 分化成不同的亚型(最显著的是祖细胞滋养层细胞、合体滋养层细胞、 SYN；和绒毛外滋养细胞；EVT)形成母胎界面，以前的数据显示 对弓形虫感染有不同程度的易感性。拟议的研究验证了弓形虫的假设 中枢神经系统的感染改变了它们的发育轨迹，促进了寄生虫的感染，从而破坏了 胎盘和胎儿发育正常。这一假说是基于初步转录组和 免疫荧光数据显示，弓形虫感染的CYTS携带的基因表达特征更多 类似于允许感染的EVT与抗感染的SYN相比。这些数据表明弓形虫-- 感染改变了细胞的命运，以牺牲另一种血统为代价，偏爱一种血统，这可能对它自己有利。在 建议研究I将使用体外双能滋养层干细胞系统和胎盘器官模型 研究1)弓形虫对胎盘滋养层细胞发育的干扰程度和 2)这对胎盘滋养细胞功能有何影响。

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