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）感染会影响1-3％的妊娠，从而导致宫内生长限制 （IUGR）和四分之一的先天感染婴儿中的永久性出生缺陷。先天性的出生缺陷 CMV疾病与唐氏综合症，胎儿酒精综合征和神经管缺陷一样频繁。 有症状的婴儿经常在新生儿时期死亡，大多数幸存者都会永久衰弱 后遗症，包括智力低下，视力丧失和感觉性耳聋。此应用程序建立在我们的 对怀孕子宫中CMV感染的了解，发育中的胎盘感染模式以及 孕产妇抗体保护。分析来自超免疫球蛋白（HIG）的胎盘的分析 先天性CMV感染的治疗表明，未处理的胎盘具有高水平的纤维化，坏死 和合成性因持续的病毒复制和慢性缺氧而结。值得注意的是，胎盘治疗 产生了许多新的绒毛和毛细血管，表明重塑和补偿性适应性。早期的希格 治疗显着降低了胎儿感染。新获得的证据，通过统计分析的支持 定量数据表明，长期暴露于抗血管生成细胞因子会损害胎盘 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 承诺作为先天性感染的早期生物标志物。另外，长期暴露于免疫抑制 病毒细胞因子可能会影响细胞迁移/侵袭，并调节胎儿的细胞免疫反应。这 长期目标是了解胎盘病毒失调的基本分子机制 低氧环境中的发育和旁分泌因子。具体目标如下。目标1。 对胎盘中绒毛膜绒毛再生有关的病毒损伤和缺氧的完整评估 来自未处理和亲密的先天性CMV感染。研究细胞外基质沉积通过胎盘沉积 导致纤维化的细胞。 AIM 2。定量母体和胎儿中的血管生成因子和拮抗剂 先天性CMV感染的样品。与胎儿结局相关的水平，以验证潜在的生物标志物 感染。在低氧条件下，抗血管生成因子在专用细胞中的研究作用。目的。 3。研究 CMVIL-10和SOCS3的机制功能失调趋化因子信号传导和下游功能。 研究可溶性CEACAM1对细胞迁移的旁分泌作用。先天性CMV中的缺氧和IUGR 感染诱导先兆子痫升高的因素。我们研究的基本知识可能 验证与胎儿结局相关的感染生物标志物。将这项研究转换为诊断测试 预防疾病的治疗干预措施可能对孕产妇和胎儿健康具有广泛的利益。