HCMV infection of human placental trophoblast and hematopoietic progenitors

人胎盘滋养层和造血祖细胞的 HCMV 感染

基本信息

批准号：
8535904
负责人：
LENORE PALMA PEREIRA
金额：
$ 54.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535904
关键词：
Address Affect Antibodies Area Birth Blood CD34 gene Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Lineage Cells Characteristics Chorionic villi Chromosomes Commit Complex Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Cytoplasm DNA Development Disease Embryo Employee Strikes Environment Epithelial Equilibrium Erythrocytes Erythroid Fibrosis First Pregnancy Trimester Geminin Goals Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Hypoxia Infection Infection prevention Infectious Agent Injury Lead Licensing Link Lymphoid Measures Modeling Molecular Mus Myelogenous Myeloid Cells Neuroglia Nuclear Protein Organ Pathogenesis Placenta Placentation Play Population Pregnancy Prevention strategy Proteins Risk Role S Phase Somatic Cell Source Stem cells Surface Syncytiotrophoblast Testing Tropism Uterus Villous Viral Virion Virus Woman Work base congenital infection cytotrophoblast embryo/fetus fetal in utero insight macrophage neutralizing monoclonal antibodies novel novel strategies pathogenic bacteria placental stem cell pluripotency prevent progenitor protein expression research study self-renewal stem cell differentiation stem cell fate specification stem cell population theories transmission process trophoblast

项目摘要

DESCRIPTION (provided by applicant): Mechanisms of transplacental transmission of human cytomegalovirus (HCMV), the leading viral cause of congenital infection affecting 1-3% of births in the U.S., are unknown. Primary maternal infection in first trimester poses a 40-50% risk of transplacental transmission and permanent birth defects in 15% of diseased babies. We propose to study HCMV infection of the human placental progenitors of the trophoblast (TB) and hematopoietic lineages, and the consequences in terms of the molecular mechanisms that dysregulate development. The Fisher group identified the early-gestation human placental stroma as a niche for cells that co-expressed markers of pluripotency and determinants of mouse TB fate, which suggested that this region is one source of human TB progenitor cells (TBPCs). They isolated these cells and developed lines of continuously self-renewing TBPCs. When cultured under conditions that triggered TB differentiation, the cells formed the mature human TB populations-multi-nucleated, transport syncytiotrophoblasts (STBs) and invasive CTBs. In the same region, the Fisher group identified hematopoietic stem cells (HSCs) as well intermediate precursors of the myeloid- and erythroid-committed lineages, suggesting active hematopoiesis. Cultured in defined medium, the CD34++CD45low HSCs contributed to erythrocytes and myeloid cells. Together these studies showed that the human placenta is a source of TBPCs that populate the chorionic villi and HSCs that might play a role in development of the hematopoietic system of the embryo/fetus. It is likely that placental HSCs also contribute to the placental Hofbauer macrophage population. TBPCs are highly susceptible to infection with a pathogenic HCMV strain that induced expression of proteins controlling cell-cycle progression and the balance between self-renewal and lineage-commitment. Upregulated molecules were mislocalized to the cytoplasm and accumulated in the virion assembly compartment. Additional experiments showed that HCMV infected placentally-derived HSCs. Here, we propose testing the theory that HCMV infection alters the balance between TBPC self-renewal and differentiation (Aim 1). We also hypothesize that infection of HSCs impairs their ability to form myeloid- and erythroid-committed lineages (Aim 2). These studies will provide new insights into viral effects on differentiation of TBPCs, which carry out the specialized functions of the placenta, and HSCs, which contribute to fetal hematopoiesis and the placental immunological barrier. Then we will use this information to determine if the same phenotypic changes are observed in placentas that were congenitally infected in utero. We will also measure the ability of human neutralizing MoAbs to protect chorionic villi from HCMV infection (Aim 3). In summary, these studies will provide new information about the effects of HCMV on TBPC and HSC self-renewal and differentiation. We also expect to gain insights into novel approaches for preventing HCMV transmission and the attendant birth defects.

描述（由申请人提供）：人类巨细胞病毒（HCMV）的移植机制是，先天性感染的主要病毒原因影响了美国的1-3％的出生。头三个月的原发性产妇感染构成了40-50％的移植传播风险和15％的患病婴儿的永久性出生缺陷。我们建议研究滋养细胞（TB）和造血谱系的人胎盘祖细胞的HCMV感染，以及在失调发展的分子机制方面的后果。 Fisher组将早期妊娠胎盘基质确定为对多能量标记和小鼠TB命运标记的细胞的利基，这表明该区域是人类TB祖细胞（TBPC）的来源之一。他们隔离了这些细胞，并开发了连续自我更新的TBPC线。当在触发结核病分化的条件下培养时，细胞形成成熟的人类TB种群 - 核核，转运合成肌细胞（STB）和侵入性CTB。在同一区域，费舍尔组鉴定出造血干细胞（HSC）以及髓样和红细胞固定的谱系的中间前体，表明活性造血症。 CD34 ++ CD45LOW HSC在定义的培养基中培养，促成红细胞和髓样细胞。这些研究共同表明，人胎盘是填充绒毛膜绒毛和HSC的TBPC的来源，可能在胚胎/胎儿的造血系统的发展中发挥作用。胎盘HSC可能也有助于胎盘霍夫鲍尔巨噬细胞种群。 TBPC高度易受致病性HCMV菌株感染，该致病性HCMV菌株诱导了控制细胞周期进展的蛋白质表达以及自我更新和谱系承诺之间的平衡。上调的分子被错误地定位到细胞质中，并积聚在病毒体组件室中。其他实验表明，HCMV感染了胎盘衍生的HSC。在这里，我们提出了测试HCMV感染改变TBPC自我更新和分化之间平衡的理论（AIM 1）。我们还假设，HSC的感染会损害其形成髓样和红细胞固定谱系的能力（AIM 2）。这些研究将提供对TBPC分化的病毒影响的新见解，TBPC的胎盘和HSC的专业功能有助于胎儿造血和胎盘免疫障碍。然后，我们将使用这些信息来确定在胎盘中是否观察到在子宫内感染的相同的表型变化。我们还将测量人类中和摩押保护绒毛膜绒毛免受HCMV感染的能力（AIM 3）。总而言之，这些研究将提供有关HCMV对TBPC和HSC自我更新和分化的影响的新信息。我们还希望能够了解防止HCMV传播和随之而来的先天缺陷的新方法。