The role of placental secreted factors in teratogenic virus infections

项目总结/摘要： 本申请的首要目标是鉴定人胎盘滋养层相关的通路，其改变 母胎对致畸病毒感染的敏感性。病毒从母体经血液传播 宿主进入胎儿隔室可能会在发育中的胚胎中引起破坏性后果。即使在 如果没有垂直传播，病毒感染可能会损害孕产妇健康并危及怀孕 结果。胎盘滋养层细胞直接与母体血液接触，主动传递因子， 可以保护母体和胎儿组织免受病毒感染或使其敏感。拟议研究 结合病毒学，免疫学和胎盘生物学的专业知识，以确定胎盘来源的内在和 以细胞类型特异性方式支持或削弱抗病毒防御的外在途径。 我们以前已经确定了胎盘滋养层细胞限制病毒感染的两种途径。这些 包括囊泡中小RNA（microRNA）和抗病毒III型干扰素（IFN）的组成性释放。 这些先前的研究表明，滋养层形成了病毒垂直传播的屏障， 与胎儿疾病相关的病毒必须绕过滋养层内在的抗病毒途径，通过 造血途径在本申请中，我们将鉴定细胞内在IFN介导的效应物，其介导 胎盘对包括ZIKV、风疹病毒（RuV）、人源性病毒（HBV）和人源性病毒（HBV）在内的一组致畸病毒的感染的抗性 巨细胞病毒（CMV）和疱疹病毒（HSV-1和HSV-2）。此外，我们将确定分泌的效应物 从人类滋养层细胞，使单核细胞对病毒感染敏感，并确定这些因素是否作用于 其它致畸病毒和其它免疫细胞群 我们已经确定了可传播的胎盘对病毒感染的抵抗力的新途径， 对病毒感染的易感性。在破译构成这些通路的潜在机制时，我们 可以阐明滋养层抵抗病毒的基础，并确定可能特别适合的细胞群。 对怀孕期间的病毒感染敏感。这些研究可以为创新的发展提供信息。 设计用于减轻和/或预防病毒感染的治疗剂，从而减少感染相关的负担， 胎儿-产妇发病率和死亡率。

PROJECT SUMMARY/ABSTRACT: The overarching goal of this application is to identify human placental trophoblast-associated pathways that alter maternal-fetal sensitivity to teratogenic virus infections. The hematogenous spread of viruses from the maternal host to the fetal compartment can induce devastating consequences in the developing embryo. Even in the absence of vertical transmission, viral infections can compromise maternal health and jeopardize pregnancy outcome. Located in direct contact with maternal blood, placental trophoblasts actively communicate factors that might both protect against or sensitize maternal and fetal tissues to viral infections. The proposed research combines expertise in virology, immunology, and placental biology to identify placental-derived intrinsic and extrinsic pathways that bolster or weaken antiviral defenses in a cell-type specific manner. We have previously identified two pathways employed by placental trophoblasts to restrict viral infections. These include the constitutive release of small RNAs (microRNAs) in vesicles and antiviral type III interferons (IFNs). These previous studies suggest that trophoblasts form a barrier to the vertical transmission of viruses and that viruses associated with fetal disease must bypass trophoblast-intrinsic antiviral pathways to be transmitted by the hematogenous route. In this application, we will identify cell intrinsic IFN-mediated effectors that mediate placental resistance to infection to a panel of teratogenic viruses including ZIKV, Rubella virus (RuV), human cytomegalovirus (CMV), and herpesviruses (HSV-1 and HSV-2). In addition, we will identify effectors secreted from human trophoblasts that sensitize monocytes to viral infections and determine whether these factors act on other teratogenic viruses and on other immune cell populations We have identified novel pathways for transmissible placental resistance to viral infections and enhanced susceptibility to viral infections. In deciphering the underlying mechanisms that constitute these pathways, we may illuminate the basis of trophoblast resistance to viruses and identify cell populations that may be particularly sensitive to viral infections during pregnancy. These studies could inform the development of innovative therapeutics designed to mitigate and/or prevent viral infections, thus reducing the burden of infection related feto-maternal morbidity and mortality.