Maternal SARS-CoV-2 infection, placenta biology, and neurodevelopmental outcomes in the offspring

项目摘要 妊娠期SARS-CoV-2感染对母体-胎盘-胎儿三联体生物学的影响程度 后代的神经发育轨迹尚不清楚。早期的研究表明，SARS-CoV-2可以诱导 胎盘改变可增加围产期不良结局的风险， 从其他感染性和炎症性疾病在怀孕和初步数据对目前的流行， 增加后代神经发育障碍（NDD）风险。该提案的长期目标是 及时确定正在进行的大流行对母亲分娩后出生的婴儿神经发育的影响， SARS-CoV-2感染。目的是分析母亲SARS-CoV-2感染， 胎盘生物学和神经发育结果，与NDD和性别的基因组风险（GRS）相互作用。 中心假设是母亲SARS-CoV-2感染和感染相关的妊娠并发症 影响大脑发育的早期路径，特别是在那些对NDD和男性具有高GRS的人中， 这些作用是由胎盘形态学和分子生物学的改变介导的。所依据的理由 建议是，完成这项工作将确定查明和可能预防国家干旱和荒漠化的关键目标， 受感染母亲的后代将通过追求以下具体目标来检验中心假设： 1)确定产前SARS-CoV-2感染后的妊娠、胎盘和新生儿结局; 2） 探讨SARS-CoV-2母体感染、NDD的GRS和胎盘分子 3）评估母亲SARS-CoV-2感染与妊娠、子代基因组学的关系 NDD的风险因素和神经发育结果。我们将采用创新的 结合胎盘组织和母体及胎儿血液分析，以及全面的心理测量测试 早期儿童神经发育的重要性。我们将比较暴露于SARS-CoV-2的妇女-胎盘-婴儿三联体 妊娠期感染与未接种疫苗和接种疫苗的对照。我们将研究如何在一个大样本中， 多种族、母亲感染和压力、NDD的GRS和性别对 通过胎盘基因/蛋白质改变介导的过程对后代的神经发育结果 表达和母体免疫激活。这项研究具有重要意义，因为它将描述 母亲SARS-CoV-2感染与后代神经发育结果之间的关系，以及 还鉴定调节、介导或作为生物标志物揭示这些的因子、分子和基因组预测因子， 关系这项工作的最接近的预期成果将是通过以下方式了解机制： 哪些母体感染、基因组风险和性别、胎盘生物学和产后因素可能有助于定义 NDD的风险。结果将立即产生积极影响，为有针对性的干预措施和指导方针提供信息 对于SARS-CoV-2暴露的妇女及其婴儿，影响临床医生如何评估和护理这些病例， 并确定妊娠期间感染NDD的母亲的后代中NDD风险的潜在生物标志物。

PROJECT SUMMARY The extent to which SARS-CoV-2 infection in pregnancy affects the biology of the maternal-placental-fetal triad and neurodevelopmental trajectory in offspring is not known. Early studies indicate that SARS-CoV-2 can induce alterations in the placenta which can increase risk for adverse perinatal outcomes and, based on knowledge from other infectious and inflammatory disorders in pregnancy and preliminary data on the current pandemic, increase risk for neurodevelopmental disorders (NDDs) in offspring. The long-term goal of this proposal is to timely identify the impact of the ongoing pandemic on the neurodevelopment of infants born following maternal SARS-CoV-2 infection. The objective is to analyze the relationships between maternal SARS-CoV-2 infection, placenta biology, and neurodevelopmental outcomes, in interaction with genomic risk (GRSs) for NDDs and sex. The central hypothesis is that maternal SARS-CoV-2 infection and infection-related pregnancy complications affect early paths of brain development, particularly in those with high GRSs for NDDs and in males, and that these effects are mediated by alterations in placenta morphology and molecular biology. The rationale underlying the proposal is that completion will define critical targets for identification and potentially prevention of NDDs in the offspring of infected mothers. The central hypothesis will be tested by pursuing the following specific aims: 1) Determine pregnancy, placental, and newborn outcomes following antenatal SARS-CoV-2 infection; 2) Investigate the relationship between SARS-CoV-2 maternal infection, GRSs for NDDs, and placenta molecular biology; 3) Evaluate the relationship between maternal SARS-CoV-2 infection in pregnancy, offspring genomic risk factors for NDDs, and neurodevelopmental outcomes. We will pursue the aims using an innovative combination of placenta tissue and maternal and fetal blood analysis, and comprehensive psychometric testing of early child neurodevelopment. We will compare woman-placenta-infant triads exposed to SARS-CoV-2 infection during pregnancy to unvaccinated and vaccinated controls. We will study how, in a large sample of multiple ethnicities, maternal infection and stress, GRSs for NDDs, and sex, adversely affect neurodevelopmental outcomes of the offspring though processes mediated by alteration in placenta gene/protein expression and maternal immune activation. The proposed research is significant, because it will characterize the relationship between maternal SARS-CoV-2 infection and neurodevelopmental outcome of the offspring, and also identify factors, molecules and genomic predictors that modulate, mediate or – as biomarkers – reveal such relationship. The proximate expected outcome of this work will be an understanding of the mechanisms through which maternal infection, genomic risk and sex, placenta biology, and postnatal factors may contribute to define risk for NDDs. The results will have an immediate positive impact to inform targeted interventions and guidelines for SARS-CoV-2 exposed women and their infants, impacting how clinicians evaluate and care for these cases, and to identify potential biomarkers of risk for NDDs in offspring of mothers with infection during pregnancy.