Innate immune signaling in placental antiviral defenses

胎盘抗病毒防御中的先天免疫信号

基本信息

批准号：
10448995
负责人：
Carolyn B Coyne
金额：
$ 70.77万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-17 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448995
关键词：
Ablation Antiviral Agents Blood Circulation Bypass Cells Cervical Chorion Chorionic villi Complement Congenital Abnormality Congenital Disorders Data Decidua Development Diamond Disease Embryo Epithelial Cells Fetal Diseases Fetal Membranes Fetus Fibroblasts Goals Health Hematogenous Hematogenous Spread Herpesviridae Human Human Herpesvirus 2 IFNAR1 gene Immune Immune signaling Immunologics Immunology In Vitro Individual Infection Infection Control Infectious Agent Inflammation Injury Interferon Receptor Interferon-alpha Interferons Knock-in Mouse Laboratories Ligands Maternal Health Maternal-Fetal Exchange Maternal-Fetal Transmission Mediating Mesenchymal Modeling Molecular Morbidity - disease rate Mothers Mucous Membrane Mus Newborn Infant Outcome Pathogenesis Pathway interactions Pattern Pattern recognition receptor Placenta Placental Biology Play Population Predisposition Pregnancy Pregnancy Outcome Pregnant Women Premature Labor Receptor Signaling Reproductive Health Research Resistance Role Route Rubella virus STAT2 gene Signal Pathway Signal Transduction Signaling Molecule Structure Syncytiotrophoblast Teratogens Therapeutic Tissues Vagina Vertical Disease Transmission Viral Virus Virus Diseases ZIKV infection Zika Virus amnion cell type design experimental study fetal fetus cell functional outcomes human tissue in vivo in vivo Model infection burden innate immune pathways innovation insight mortality pathogen pathogenic virus prevent receptor expression response stillbirth trophoblast vaginal mucosa viral transmission virology

Ablation Antiviral Agents Blood Circulation Bypass Cells Cervical Chorion Chorionic villi Complement Congenital Abnormality Congenital Disorders Data Decidua Development Diamond Disease Embryo Epithelial Cells Fetal Diseases Fetal Membranes Fetus Fibroblasts Goals Health Hematogenous Hematogenous Spread Herpesviridae Human Human Herpesvirus 2 IFNAR1 gene Immune Immune signaling Immunologics Immunology In Vitro Individual Infection Infection Control Infectious Agent Inflammation Injury Interferon Receptor Interferon-alpha Interferons Knock-in Mouse Laboratories Ligands Maternal Health Maternal-Fetal Exchange Maternal-Fetal Transmission Mediating Mesenchymal Modeling Molecular Morbidity - disease rate Mothers Mucous Membrane Mus Newborn Infant Outcome Pathogenesis Pathway interactions Pattern Pattern recognition receptor Placenta Placental Biology Play Population Predisposition Pregnancy Pregnancy Outcome Pregnant Women Premature Labor Receptor Signaling Reproductive Health Research Resistance Role Route Rubella virus STAT2 gene Signal Pathway Signal Transduction Signaling Molecule Structure Syncytiotrophoblast Teratogens Therapeutic Tissues Vagina Vertical Disease Transmission Viral Virus Virus Diseases ZIKV infection Zika Virus amnion cell type design experimental study fetal fetus cell functional outcomes human tissue in vivo in vivo Model infection burden innate immune pathways innovation insight mortality pathogen pathogenic virus prevent receptor expression response stillbirth trophoblast vaginal mucosa viral transmission virology

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项目摘要

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.

该应用的总体目标是确定人类胎盘先天免疫途径和因素改变母亲对致病病毒感染的敏感性。病毒从母体循环到胎儿可能会引起毁灭性的后果，妥协孕产妇的健康，并危害妊娠结局。胎盘是主要的免疫学和物理病毒从母体循环以及阴道和宫颈粘膜传播的障碍。然而，尽管这一障碍很重要，但关于先天免疫途径的知之甚少胎盘感应并应对病毒感染。 Coyne和Diamond的拟议研究实验室结合了病毒学，免疫学和胎盘生物学方面的专业知识，以识别胎盘衍生以胎盘型特异性方式增强抗病毒防御的先天免疫途径。我们先前已经确定了胎盘滋养细胞所采用的途径以限制病毒感染。这些包括保护母体和胎儿的抗病毒III型干扰素（IFN）的本构释放从病毒感染中衍生的细胞。这些先前的研究表明，滋养细胞构成了天生的IFN介导的病毒垂直传播和与胎儿疾病相关的病毒的障碍必须绕过这些滋养细胞的内在途径是经盆腔传播的。在此应用程序中，我们将定义天生免疫抗病毒途径，胎盘衍生的胎盘成分（包括绒毛膜和胎儿）成分羊膜和绒毛膜，感知并反应已知的致病病毒感染，包括寨卡病毒（ZIKV），风疹病毒（RUV）和疱疹病毒-2（HSV-2）。这些研究将利用个人和互补专门从事病毒学（CC和MD），免疫学（CC和CC和 MD），胎盘生物学（CC）和母体 - 狂热传播（MD）的体内建模。此外，我们将定义不同的IFN类型（I型和III）的机制影响胎盘抗病毒信号和胎盘损害。在解密构成胎盘衍生的抗病毒先天免疫途径的基本机制时，我们可能会阐明胎盘敏感性或对病毒的抗性的基础，并确定可能怀孕期间对病毒感染特别敏感。这些研究可以告知旨在减轻和/或预防病毒感染或炎症引起的损伤的创新治疗药，因此减轻感染相关的胎儿发病率和死亡率的负担。