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

• 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
• 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

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）：原发性人巨细胞病毒（HCMV）感染影响1-3%的妊娠，导致25%的先天性感染婴儿宫内生长受限（IUGR）和永久性出生缺陷。有症状的婴儿往往在新生儿期死亡，大多数幸存者都有永久性的衰弱后遗症，包括智力迟钝、视力丧失和感音神经性耳聋。该应用程序建立在我们对发育中的胎盘中HCMV感染模式的了解以及通过研究体外感染和子宫内先天性感染的人胎盘获得的母源抗体的保护。由于宿主范围的限制，病毒如何传播到胎盘以及免疫防御如何减少HCMV复制仍未得到解决。建立人胎盘绒毛移植肾包膜下重度联合免疫缺陷（SCID）小鼠模型，在体内研究胎儿细胞滋养细胞对血管的影响。在人胎盘植入物中，细胞滋养细胞分化，强烈侵袭小动脉并深入肾实质。这些细胞诱导了戏剧性的淋巴管生成反应和淋巴管的形成，与人类蜕膜相当。我们已经开始研究人类胎盘和蜕膜异种移植物中的HCMV感染，并将其与子宫-胎盘界面的病毒复制进行比较。初步研究表明，致病菌株VR1814感染细胞滋养细胞，并以与先天性感染胎盘相似的模式复制。与胎盘植入物相比，病毒在受感染的蜕膜植入物中广泛传播，这表明不同的组织环境会影响体内的复制水平。我们的主要假设是：(i) HCMV感染可以在SCID小鼠的人胎盘模型中研究，（ii）致病菌株可以用来确定组织微环境中细胞病毒趋向性的决定因素，以及（iii）中和抗HCMV抗体减少胎盘中的感染。进一步，我们提出IFN-？在体内调节病毒复制。这一假设的证实将直接关系到预防先天性感染和疾病的临床应用。具体目的如下。目的1。研究HCMV在SCID小鼠胎盘和蜕膜植入物模型中的复制和病毒传播。目标2。在病毒中和抗体和IFN-存在下评估HCMV在人胎盘和蜕膜植入物中的复制表达式。尤其重要的是，临床应用将牢固地建立人类胎盘植入物的效用，以评估HCMV的发病机制和新的抗病毒策略，以减少子宫和胎盘微环境中的感染。