Compensatory placental development after treatment for congenital CMV infection

先天性巨细胞病毒感染治疗后的代偿性胎盘发育

• 批准号: 7681449
• 负责人: LENORE PALMA PEREIRA
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2009-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681449
• 关键词: Affect; Aftercare; Amniocentesis; Amniotic Fluid; Angiogenesis Inhibitors; Angiogenic Factor; Antibody Avidity; Antigen-Antibody Complex; Area; Arteries; Avidity; Biological Markers; Birth; Blindness; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Brain Injuries; CEACAM1; Cells; Child; Chorionic villi; Chorioretinitis; Chronic; Clinical Trials; Condition; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; Data; Decidua; Decidual Cell; Deposition; Development; Diagnostic tests; Disease; Down Syndrome; Early Diagnosis; Endothelial Cells; Environment; Evaluation; Exposure to; Extracellular Matrix; Fetal Alcohol Syndrome; Fetal Growth Retardation; Fetus; Fibrosis; Functional disorder; Globulins; Goals; Health; Hospitals; Hypoxia; Immune response; Immunoglobulin G; Immunosuppressive Agents; Incidence; Infant; Infection; Infiltration; Integrins; Invaded; Knowledge; Live Birth; Maternal antibody; Matrix Metalloproteinases; Mental Retardation; Molecular; Mothers; Natural regeneration; Necrosis; Neonatal; Neural Tube Defects; Neurologic; Nutrient; Organ; Outcome; Oxygen; Pattern; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnant Uterus; Pregnant Women; Prevention; Prospective Studies; Reporting; Research; Risk; Role; Sample Size; Sampling; Sensorineural Hearing Loss; Signal Transduction; Site; Stimulus; Surface; Survivors; Syncytiotrophoblast; Testing; Therapeutic Intervention; Time; Translations; Umbilical Cord Blood; United States; Vascular Endothelial Growth Factors; Villus; Viral; Virion; Virus; Virus Diseases; Virus Replication; Week; Woman; capillary; cell motility; chemokine; congenital cytomegalovirus; congenital infection; cytokine; cytotrophoblast; disability; fetal; fetal blood; fetal infection; fetus hypoxia; hearing impairment; immune function; improved; inhibitor/antagonist; insight; maternal serum; migration; neonatal Fc receptor; novel; paracrine; pregnancy disorder; prenatal; prevent; receptor; response; stem; transmission process

Primary cytomegalovirus (CMV) infection affects 1-3% of pregnancies, causing intrauterine growth restriction (IUGR) and permanent birth defects in a quarter of congenitally infected babies. Birth defects from congenital CMV disease are as frequent as those from Down syndrome, fetal alcohol syndrome and neural tube defects. Symptomatic infants often die 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 CMV infection in the pregnant uterus, patterns of infection in the developing placenta, and protection by maternal antibodies. Analysis of placentas from a clinical trial of hyperimmune globulin (HIG) for treatment of congenital CMV infection showed that untreated placentas had high levels of fibrosis, necrosis and syncytial knotting from sustained viral replication and chronic hypoxia. Remarkably, HIG-treated placentas generated many new villi and capillaries, indicating remodeling and compensatory adaptation. Early HIG treatment significantly reduced fetal infection. Newly acquired evidence, supported by statistical analysis of quantitative data, shows that chronic exposure to anti-angiogenic cellular factors can impair placental responses to hypoxia. These factors, concentrated in amniotic fluid and detected in maternal sera, hold promise as early biomarkers of congenital infection. In addition, chronic exposure to an immunosuppressive viral cytokine may affect cell migration/invasion and modulate cellular immune responses in the fetus. The long-term goal is to understand fundamental molecular mechanisms underlying viral dysregulation of placental development and paracrine factors in a hypoxic environment. The specific aims are as follows. Aim 1. Complete evaluation of viral damage and hypoxia associated with chorionic villus regeneration in placentas from untreated and HIG-treated congenital CMV infection. Study extracellular matrix deposition by placental cells that contributes to fibrosis. Aim 2. Quantify angiogenic factors and antagonists in maternal and fetal samples from congenital CMV infection. Correlate levels with fetal outcome to verify potential biomarkers of infection. Study effects of anti-angiogenic factors in specialized cells under hypoxic conditions. Aim. 3. Study mechanisms whereby cmvIL-10 and SOCS3 dysregulate chemokine signaling and downstream functions. Investigate paracrine effects of soluble CEACAM1 on cell migration. Hypoxia and IUGR in congenital CMV infection induce a subset of factors elevated in preeclampsia. Fundamental knowledge from our research could verify biomarkers of infection that correlate with fetal outcome. Translation of this research to diagnostic tests and therapeutic interventions to prevent disease could prove broadly beneficial to maternal and fetal health.

原发性巨细胞病毒（CMV）感染影响1-3%的妊娠，导致宫内生长受限 （IUGR）和永久性出生缺陷的四分之一的先天性感染婴儿。先天性出生缺陷 巨细胞病毒病与唐氏综合征、胎儿酒精综合征和神经管缺陷一样常见。 有症状的婴儿往往在新生儿期死亡，大多数幸存者有永久性衰弱 后遗症包括智力迟钝、视力丧失和感音神经性耳聋。此应用程序基于我们的 了解妊娠子宫中的CMV感染，胎盘发育中的感染模式，以及 母亲抗体的保护。来自高免疫球蛋白（HIG）用于妊娠结局的临床试验的胎盘分析 先天性CMV感染的治疗显示，未经治疗的胎盘有高水平的纤维化，坏死， 以及持续病毒复制和慢性缺氧导致的合胞体打结。值得注意的是，高剂量处理的胎盘 产生了许多新的绒毛和毛细血管，表明重塑和代偿性适应。早期HIG 治疗显著降低了胎儿感染。新获得的证据，得到以下统计分析的支持： 定量数据显示，长期暴露于抗血管生成细胞因子可损害胎盘 对缺氧的反应这些因素，集中在羊水中，并在母体血清中检测到， 有望成为先天性感染的早期生物标志物。此外，长期接触免疫抑制剂 病毒细胞因子可影响细胞迁移/侵袭并调节胎儿的细胞免疫应答。的 长期目标是了解胎盘病毒失调的基本分子机制， 发育和旁分泌因子。具体目标如下。目标1. 病毒损伤和缺氧与胎盘绒毛再生相关性的全面评估 未经治疗和高度治疗的先天性CMV感染。胎盘细胞外基质沉积的研究 导致纤维化的细胞目标2.定量母体和胎儿中的血管生成因子和拮抗剂 先天性CMV感染的样本。将水平与胎儿结局相关联，以验证 感染研究低氧条件下特化细胞中抗血管生成因子的作用。瞄准3.研究 cmvIL-10和SOCS 3失调趋化因子信号传导和下游功能的机制。 研究可溶性CEACAM 1对细胞迁移的旁分泌作用。先天性巨细胞病毒缺氧与胎儿宫内发育迟缓 感染诱导先兆子痫中一部分因子升高。我们研究的基础知识可以 验证与胎儿结局相关的感染生物标志物。将本研究转化为诊断测试 预防疾病的治疗干预措施可以证明对母亲和胎儿的健康是广泛有益的。