HCMV infection and immune modulation in a human placentation model in SCID mice

SCID 小鼠人类胎盘模型中的 HCMV 感染和免疫调节

基本信息

批准号：
8092875
负责人：
LENORE PALMA PEREIRA
金额：
$ 22.94万
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：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8092875
关键词：
Affect Animal Model Antibodies Antiviral Agents Apoptosis Avidity Blindness Blood Circulation Blood Vessels Cell Adhesion Molecules Cell-Matrix Junction Cells Chorionic villi Clinical Collagen Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Decidua Decidual Cell Defect Dendritic Cells Deposition Development Diagnostic tests Disease Endometrial Endometrium Endothelial Cells Endothelium Environment Epithelial Cells Erythrocytes Fetal Growth Retardation Fetal Tissues Fibroblasts First Pregnancy Trimester Focal Infection Gelatinase B Gland Glean Glycoproteins HLA G antigen Human Immune Immunity Immunoglobulin G Implant In Vitro Incidence Infant Infection Integrins Interferons Intervention Invaded Island Kidney Knowledge Lead Live Birth Liver Lymphatic Lymphatic Endothelial Cells Lymphatic vessel MHC Class I Genes Maternal antibody Mediating Mental Retardation Modeling Molecular Mus Natural Killer Cells Neonatal Neurologic Outcome Passive Immunization Pathogenesis Pattern Placenta Placentation Pregnancy Prevention Proteins Recurrence Reporting Retinal Diseases Risk Role SCID Mice Sensorineural Hearing Loss Severe Combined Immunodeficiency Site Staging Surface Survivors Syncytiotrophoblast Thymus Gland Tissues Transplantation Tropism United States Up-Regulation Vesicle Villous Villus Viral Viral Proteins Virion Virus Virus Diseases Virus Replication Woman Xenograft procedure arteriole capsule clinical application congenital infection cytokine cytotrophoblast deafness fetal fetal infection immunoregulation in utero in vivo interest macrophage migration mouse model neonatal Fc receptor neutralizing antibody neutralizing monoclonal antibodies neutrophil novel novel strategies practical application prevent progenitor public health relevance receptor response transmission process

项目摘要

DESCRIPTION (provided by applicant): Primary human cytomegalovirus (HCMV) infection affects 1-3% of pregnancies, causing intrauterine growth restriction (IUGR) and permanent birth defects in 25% of congenitally infected babies. Symptomatic infants often succumb in the neonatal period, and most survivors have permanent debilitating sequelae, including mental retardation, vision loss and sensorineural deafness. This application builds on our knowledge of patterns of HCMV infection in the developing placenta and protection by maternal antibodies gained by studying the human placenta infected in vitro and congenitally infected in utero. How virus disseminates to the placenta and how immune defenses reduce HCMV replication are still unresolved due to the extreme host range restriction. A new severe-combined immunodeficient (SCID) murine model of human placental villi transplanted beneath the kidney capsule was established to study the vascular effects of fetal cytotrophoblasts in vivo. In human placental implants, cytotrophoblasts differentiate, undergo robust invasion of arterioles and migrate deep into the kidney parenchyma. The cells induce a dramatic lymphangiogenic response and formation of lymphatic vessels comparable to the human decidua. We have begun to study HCMV infection in human placental and decidual xenografts, also recently developed, and compare these with viral replication at the uterine-placental interface. Preliminary studies showed that the pathogenic strain VR1814 infected cytotrophoblasts and replicated in patterns that were comparable to those seen in congenitally infected placentas. In contrast to placental implants, virus spread extensively in infected decidual implants suggesting that different tissue environments affect levels of replication in vivo. Our overarching hypothesis is that (i) HCMV infection can be studied in a model of human placentation in SCID mice, (ii) pathogenic strains can be used to define determinants for viral tropism in cells within their tissue microenvironment, and (iii) neutralizing anti-HCMV antibodies reduce infection in the placenta. Further, we propose that IFN-? modulates viral replication in vivo. Confirmation of this hypothesis will be directly relevant to clinical applications for the prevention of congenital infection and disease. The specific aims are as follows. Aim 1. Study HCMV replication and virus dissemination in placental and decidual implants in a model of human placentation in SCID mice. Aim 2. Evaluate HCMV replication in human placental and decidual implants in the presence of virus neutralizing antibodies and IFN-? expression. Especially important for clinical applications will be firmly establishing the utility of human placental implants to evaluate HCMV pathogenesis and novel antiviral strategies tailored to reduce infection in the uterine and placental microenvironments. PUBLIC HEALTH RELEVANCE: Information from studies of HCMV infection in human placental and decidual implants in the severe combined immunodeficiency (SCID) mouse model will lead directly to practical application of new clinical interventions that reduce viral replication at the uterine-placental interface, assess viral proteins with potential use in diagnostic tests, identify viral glycoproteins that elicit potent neutralizing antibodies, and develop novel strategies to bolster innate immune defenses in the placenta.

描述（由申请人提供）：原发性人类巨细胞病毒（HCMV）感染会影响1-3％的怀孕，导致宫内内生长限制（IUGR）和25％的先天性感染婴儿的永久性先天缺陷。有症状的婴儿经常在新生儿时期屈服，大多数幸存者都有永久性的后遗症，包括智力低下，视力丧失和感觉性耳聋。该应用基于我们对发育中的胎盘中HCMV感染模式的了解，并通过研究在子宫内感染了体外感染和先天性感染的孕产妇抗体。由于极端的宿主范围限制，病毒如何传播到胎盘以及免疫防御能力如何减少HCMV复制。建立了一种新的严重混合的免疫缺陷（SCID）鼠模型，该模型的人胎盘绒毛在肾囊下面移植了，以研究体内胎儿细胞增多质细胞的血管作用。在人胎盘植入物中，细胞增多质细胞分化，可强大的动脉侵袭并深入肾脏实质。细胞诱导与人deciDUA相当的淋巴血管的戏剧性淋巴生成反应和形成。我们已经开始研究人类胎盘和dec骨异种移植物中的HCMV感染，最近也开发了，并将其与子宫 - 斑点界面的病毒复制进行了比较。初步研究表明，致病菌株VR1814感染的细胞质细胞，并以与先天感染的胎盘相当的模式复制。与胎盘植入物相反，病毒在感染的deci植物中广泛扩散，这表明不同的组织环境会影响体内复制水平。我们的总体假设是（i）可以在SCID小鼠的人体胎盘模型中研究HCMV感染，（ii）致病菌株可用于定义其组织微环境中细胞中病毒性疗法的决定因素，并且（iii）中和抗HCMV抗体中和抗HCMV抗体降低了脚部感染。此外，我们提出了IFN-？调节体内病毒复制。确认该假设将与预防先天性感染和疾病的临床应用直接相关。具体目标如下。 AIM 1。在SCID小鼠的人体胎盘模型中研究HCMV复制和病毒传播。 AIM 2。在存在中和抗体和IFN-的情况下，在人胎盘和decIDAIM植入物中评估HCMV复制。表达。对于临床应用而言，尤其重要的是，将牢固确定人胎盘植入物评估HCMV发病机理和量身定制的新型抗病毒策略，以减少子宫和胎盘微环境中的感染。公共卫生相关性：从严重组合免疫缺陷（SCID）小鼠模型中HCMV感染研究的信息中，将直接导致新的临床干预措施的实际应用，这些新临床干预措施可减少病毒式复制，从而在子宫植物界面上评估病毒蛋白在诊断效果中的潜在使用，以评估病毒蛋白的使用，并识别诊断剂的病毒式剂量剂量，这些策略是诊断剂的potort potort potort potort potort potort potoptir potoptir potoptir potoptir potoptir potoptir potoptip在胎盘中加强先天免疫防御。