Innate immune signaling in placental antiviral defenses

胎盘抗病毒防御中的先天免疫信号

• 批准号: 10662462
• 负责人: Carolyn B Coyne
• 金额: $ 68.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10662462
• 关键词: Ablation; Bypass; Cells; Cervical; Chorion; Chorionic villi; Circulation; Complement; Congenital Abnormality; Congenital Disorders; Data; Decidua; Development; Diamond; Disease; Disparate; Embryo; Epithelial Cells; Fetal Diseases; Fetal Membranes; Fetus; Fibroblasts; Goals; Health; Hematogenous; Hematogenous Spread; Herpesviridae; Human; IFNAR1 gene; Immune; Immune signaling; Immunologics; Immunology; In Vitro; Individual; Infection; Infection Control; Infectious Agent; Inflammation; Injury; Interferon Receptor; Interferon Type I; 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 Induction; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; Syncytiotrophoblast; Teratogens; Therapeutic; Tissues; Vagina; Vertical 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; permissiveness; prevent; receptor expression; response; stillbirth; transmission process; trophoblast; vaginal mucosa; viral transmission; virology

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 改变母胎对致畸病毒感染的敏感性。病毒通过血行传播 母体循环到胎儿可能会对发育中的胚胎造成毁灭性的后果，妥协 孕产妇健康，并危害妊娠结局。胎盘是主要的免疫和生理器官 阻止病毒从母体循环以及阴道和宫颈粘膜传播。然而， 尽管这一屏障很重要，但人们对先天免疫途径知之甚少。 胎盘感知病毒感染并做出反应。 Coyne 和 Diamond 提出的研究 实验室结合了病毒学、免疫学和胎盘生物学的专业知识来鉴定胎盘来源的 以胎盘细胞类型特异性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用于限制病毒感染的途径。这些 包括抗病毒 III 型干扰素 (IFN) 的持续释放，可保护母体和胎儿 来自病毒感染的细胞。这些先前的研究表明滋养层细胞形成先天的干扰素介导的 病毒垂直传播的屏障，与胎儿疾病相关的病毒必须绕过这些屏障 滋养层内在途径经胎盘传播。在这个应用程序中，我们将定义先天的 胎盘的胎儿来源成分（包括绒毛膜绒毛和绒毛膜）通过免疫抗病毒途径 羊膜和绒毛膜，感知并响应已知致畸病毒的感染，包括寨卡病毒（ZIKV）， 风疹病毒 (RuV) 和疱疹病毒 2 (HSV-2)。这些研究将利用个体和互补的 Coyne 和 Diamond 实验室的专业知识，专门从事病毒学（CC 和 MD）、免疫学（CC 和 MD） MD）、胎盘生物学（CC）和母胎传播体内模型（MD）。此外，我们将定义 不同类型 IFN（I 型和 III 型）影响胎盘抗病毒信号和胎盘的机制 损害。 在破译构成胎盘源性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，并确定可能的细胞群 怀孕期间对病毒感染特别敏感。这些研究可以为开发提供信息 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，从而 减少感染相关的胎儿-孕产妇发病率和死亡率的负担。