Viral-induced placental impairment

描述：（由申请人提供）绒毛外的浅侵入 滋养层细胞进入子宫壁减少胎盘灌注， 胎盘功能障碍，但浅胎盘侵入的原因是 未知有待检验的假设是，侵袭性滋养层细胞的感染 腺相关病毒（AAV）和其他常见病毒 导致产科并发症， 胎盘功能障碍，包括自发性流产、胎儿生长 限制和先兆子痫。以前，AAV被证明能够感染 未分化和终末分化的滋养层细胞。AAV及其 辅助病毒（即，腺病毒、乳头瘤病毒、疱疹病毒，以及 在流产的滋养层细胞中发现了巨细胞病毒， 早产胎膜早破妇女的巨噬细胞。一 胎盘病毒感染与病理异常的关系 在胎儿生长受限的病例中报告了AAV DNA，在胎儿生长受限的病例中发现了AAV DNA。 先兆子痫病例（11/35例）和自发性 早产（8/19例）。最后，在第一次测试中， 筛选妊娠三个月的抗-AAV抗体，和原代AAV 感染（IgM抗体的存在）与增加 自然流产风险（P=0.03）。在本建议中，病例对照 将进行研究，以确定AAV感染是否与 一系列不良生殖结果，体外实验将 进行测试的假设，病毒感染诱导病理 损害胎盘侵入子宫壁的病变。三个具体 目的是：1）使用基于PCR的分析进行病例对照研究 比较胎盘病毒感染的发生率和相关的病理变化， 妊娠合并胎儿生长受限的妇女的病变 和/或重度先兆子痫（病例）和对照; 2）进行巢式 病例对照研究，其中妊娠前三个月的母体血清 妊娠期筛查抗AAV及其辅助病毒的抗体， 将早期母体病毒感染与归因于 胎盘功能障碍; 3）确定AAV和辅助病毒的能力， 体外感染绒毛外滋养层细胞系，并确定病理 与这些细胞和绒毛外植体的病毒感染相关的影响。 这些实验将提供深入了解病毒感染的作用， 胎盘功能障碍的发病机制。

DESCRIPTION: (Provided By Applicant) Shallow invasion by the extravillous trophoblast into the uterine wall reduces placental perfusion and results in placental dysfunction, but the causes of shallow placental invasion are unknown. The hypothesis to be tested is that infection of invasive trophoblast early in gestation by adeno-associated virus (AAV) and other common viruses that help AAV to replicate causes obstetric complications that result from placental dysfunction, including spontaneous miscarriage, fetal growth restriction, and preeclampsia. Previously, AAV was shown to be able to infect undifferentiated and terminally differentiated trophoblast cells. AAV and its helper viruses (i.e., adenovirus, papillomavirus, herpesvirus, and cytomegalovirus) were discovered in trophoblast cells from miscarriages and in amniocytes from women with preterm premature rupture of the membranes. A relationship between placental viral infections and pathologic abnormalities was reported in cases of fetal growth restriction, and AAV DNA was found in placental tissue from cases of preeclampsia (11/35 cases) and spontaneous preterm birth (8/19 cases). Finally, the serum of 90 women during the first trimester of pregnancy was screened for anti-AAV antibodies, and primary AAV infections (the presence of IgM antibodies) were associated with an increased risk of spontaneous miscarriage (P=0.03). In this proposal, case-control studies will be conducted to determine if AAV infection is associated with a spectrum of adverse reproductive outcomes, and in vitro experiments will be performed to test the hypothesis that viral infection induces pathologic lesions which impair placental invasion of the uterine wall. Three specific aims are proposed: 1) to conduct a case-control study using PCR-based analyses to compare the incidence of placental viral infection and associated pathologic lesions in women whose pregnancies are complicated by fetal growth restriction and/or severe preeclampsia (cases) and controls; 2) to conduct a nested case-control study in which maternal serum during the first trimester of pregnancy is screened for antibodies against AAV and its helper viruses, to correlate early maternal viral infection with adverse outcomes attributed to placental dysfunction; 3) to determine the ability of AAV and helper viruses to infect extravillous trophoblast cell lines in vitro and define the pathologic effects associated with viral infection of these cells and villous explants. These experiments will provide insights into the role of viral infection in the pathogenesis of placental dysfunction.