Innate immune signaling in placental antiviral defenses

这项应用的首要目标是识别人类胎盘先天免疫途径和因素 改变母婴对致畸病毒感染的敏感性。病毒的血源性传播 母体循环到胎儿会对发育中的胚胎造成毁灭性的后果，损害 孕妇健康，并危及妊娠结局。胎盘是一种主要的免疫学和生理 阻止病毒从母体循环以及阴道和宫颈粘膜传播。然而， 尽管这种屏障很重要，但人们对先天免疫途径知之甚少。 胎盘感知病毒感染，并对病毒感染做出反应。科因和戴蒙德提出的研究 实验室结合病毒学、免疫学和胎盘生物学的专业知识来鉴定胎盘来源 以胎盘细胞类型特有的方式增强抗病毒防御的先天免疫途径。 我们之前已经确定了胎盘滋养层细胞用来限制病毒感染的途径。这些 包括结构性释放的抗病毒III型干扰素(IFN)，它可以保护母亲和胎儿。 来自病毒感染的衍生细胞。这些先前的研究表明，滋养层细胞形成一种天然的干扰素介导的 病毒垂直传播的障碍，与胎儿疾病相关的病毒必须绕过这些障碍 滋养层细胞通过胎盘传播的内在途径。在本应用程序中，我们将定义先天的 免疫抗病毒途径胎盘的胎儿来源的成分，包括绒毛和 羊膜和绒毛，感知已知的致畸病毒感染并对其做出反应，包括寨卡病毒(ZIKV)， 风疹病毒(RUV)和疱疹病毒-2(HSV-2)。这些研究将利用个体和互补性 科因和戴蒙德实验室的专业知识，他们专门从事病毒学(CC和MD)、免疫学(CC和 MD)、胎盘生物学(CC)和母婴传播的活体模型(MD)。此外，我们还将定义 不同类型干扰素(I型和III型)影响胎盘抗病毒信号和胎盘的机制(S) 损坏。 在破译构成胎盘来源的抗病毒先天免疫途径的潜在机制时， 我们可以阐明胎盘对病毒的敏感性或抵抗力的基础，并识别可能 对怀孕期间的病毒感染特别敏感。这些研究可以为发展 旨在减轻和/或预防病毒感染或炎症引起的损伤的创新疗法，因此 减少与母婴发病率和死亡率有关的感染负担。

The overarching goal of this application is to identify human placental innate immune pathways and factors that alter maternal-fetal sensitivity to teratogenic virus infections. The hematogenous spread of viruses from the maternal circulation to the fetus can induce devastating consequences in the developing embryo, compromise maternal health, and jeopardize pregnancy outcome. The placenta is a primary immunological and physical barrier to the spread of viruses from both the maternal circulation and the vaginal and cervical mucosa. However, despite the importance of this barrier, relatively little is known regarding the innate immune pathways by which the placenta senses and responds to viral infections. The proposed research by the Coyne and Diamond laboratories combines expertise in virology, immunology, and placental biology to identify placental-derived innate immune pathways that bolster antiviral defenses in a placental cell-type specific manner. We have previously identified pathways employed by placental trophoblasts to restrict viral infections. These include the constitutive release of antiviral type III interferons (IFNs), which protect both maternal- and fetal- derived cells from viral infections. These previous studies suggest that trophoblasts form an innate IFN-mediated barrier to the vertical transmission of viruses and that viruses associated with fetal disease must bypass these trophoblast intrinsic pathways to be trans-placentally transmitted. In this application, we will define the innate immune antiviral pathways by which fetal-derived components of the placenta, including chorionic villi and the amnion and chorion, sense and respond to infection by known teratogenic viruses, including Zika virus (ZIKV), Rubella virus (RuV), and herpesvirus-2 (HSV-2). These studies will utilize the individual and complementary expertise of the Coyne and Diamond laboratories, who specialize in virology (CC and MD), immunology (CC and MD), placental biology (CC), and in vivo modeling of maternal-fetal transmission (MD). In addition, we will define the mechanism(s) by which disparate IFN types (type I and III) impact placental antiviral signaling and placental damage. In deciphering the underlying mechanisms that constitute placental-derived antiviral innate immune pathways, we may illuminate the basis of placental sensitivity or 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 or inflammation-induced injury, thus reducing the burden of infection related feto-maternal morbidity and mortality.