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

项目总结 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 而后代的神经发育轨迹尚不清楚。早期研究表明，SARS-CoV-2可以诱导 胎盘的改变会增加不良围产期结局的风险，并且根据知识 从怀孕期间的其他传染病和炎症性疾病以及关于当前大流行的初步数据， 增加后代患神经发育障碍(NDDS)的风险。这项提议的长期目标是 及时确定持续大流行对以下婴儿神经发育(ND)的影响 母亲感染SARS-CoV-2。目的是分析母亲SARS-CoV-2与 感染、胎盘生物学和ND结局，与NDDS和性行为的基因组风险(GRS)相互作用。这个 中心假设是母亲感染SARS-CoV-2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NDDS和男性GRS高的人群中，这些 影响是通过胎盘形态和分子生物学的改变来调节的。其背后的理由是 提议的是，完成工作将确定查明和潜在地预防非传统药物的关键目标 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) 确定产前感染SARS-CoV-2后的妊娠、胎盘和新生儿结局；2) SARS-CoV-2母体感染与NDDS GRS及胎盘分子关系的研究 3)评价孕期母体感染SARS-CoV-2与子代基因组的关系 NDDS和ND结果的危险因素。我们将使用创新的胎盘组合来实现这些目标 组织、母体和胎儿血液分析，以及早期儿童ND的综合心理测试。我们会 比较未接种疫苗和接种疫苗的妇女-胎盘-婴儿三合一感染SARS-CoV-2的情况 怀孕到未接种疫苗和接种疫苗的对照组。我们将研究，在一个多种族的大样本中， 孕产妇感染和压力、健康的社会决定因素、非传染性疾病的GRSs和性别，都会产生不利影响 胎盘基因/蛋白改变对后代神经发育的影响 表达和母体免疫激活。这项拟议的研究意义重大，因为它将 母体SARS-CoV-2感染与子代神经发育结局的关系 还要确定调节、调节或--作为生物标记物--揭示这种情况的因素、分子和基因组预测因子 两性关系。这项工作的近期预期成果将是通过以下途径了解这些机制 哪些母体感染、基因组风险和性别、胎盘生物学和出生后因素可能有助于确定 NDDS的风险。结果将立即产生积极影响，为有针对性的干预和指导方针提供信息 对于接触SARS-CoV-2的妇女及其婴儿，影响临床医生评估和护理这些病例的方式， 并确定孕期感染母亲的后代中可能存在的NDDS风险的生物标志物。

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 (ND) 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 ND 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 ND 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 ND. We will compare unvaccinated and vaccinated 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, social determinants of health, 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.