The role of placental secreted factors in teratogenic virus infections

胎盘分泌因子在致畸病毒感染中的作用

• 批准号: 9789679
• 负责人: Carolyn B Coyne
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2020-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789679
• 关键词: Antiviral Agents; Binding; Bioinformatics; Blood; Blood Circulation; Bypass; CD14 gene; Cells; Chorionic villi; Complex; Congenital Disorders; Cytomegalovirus; Data; Development; Embryo; Fetal Diseases; Fetal Tissues; Genes; Genetic; Goals; Hematogenous; Hematogenous Spread; Herpesviridae; Herpesvirus 1; Human; Human Herpesvirus 2; Immune; Immunization; Immunologics; Immunology; Infection; Interferon-alpha; Interferon-beta; Interferons; Maternal Health; Maternal-Fetal Exchange; Mediating; MicroRNAs; Morbidity - disease rate; Mus; Pathway interactions; Placenta; Placental Biology; Play; Population; Predisposition; Pregnancy; Pregnancy Outcome; Pregnant Women; Recombinants; Research; Resistance; Resistance to infection; Role; Route; Rubella virus; Signal Transduction; Small RNA; Syncytiotrophoblast; Teratogens; Therapeutic; Vertical Disease Transmission; Vesicle; Viral; Virus; Virus Diseases; Work; ZIKV infection; Zika Virus; autocrine; base; cell type; cytokine; design; fetal; fetus cell; in vivo; innovation; insight; monocyte; mortality; novel; paracrine; pathogen; prevent; receptor; response; therapeutic development; transcriptome sequencing; trophoblast; viral transmission; virology

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.

项目摘要/摘要： 这项应用的首要目标是确定人类胎盘滋养层细胞相关的改变路径 母婴对致畸病毒感染的敏感性。母婴传播病毒的血源性传播 寄主到胎儿隔室会对发育中的胚胎造成毁灭性的后果。即使是在 如果没有垂直传播，病毒感染会危及产妇健康并危及妊娠 结果。胎盘滋养层细胞位于与母体血液直接接触的位置，活跃地传递 可能既保护孕妇和胎儿组织免受病毒感染，也可能使其对病毒感染敏感。拟议的研究 结合病毒学、免疫学和胎盘生物学的专业知识，鉴定胎盘来源的固有和 以特定细胞类型的方式增强或减弱抗病毒防御的外在途径。 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两条途径。这些 包括小RNA(MicroRNAs)在囊泡中的结构性释放和抗病毒III型干扰素(IFN)。 这些先前的研究表明，滋养层细胞对病毒的垂直传播形成了一种屏障， 与胎儿疾病相关的病毒必须绕过滋养层固有的抗病毒途径才能通过 血液生成途径。在这一应用中，我们将识别细胞内的干扰素介导的效应器 胎盘对一组致畸病毒包括ZIKV、风疹病毒(RUV)、人类 巨细胞病毒(CMV)和疱疹病毒(HSV-1和HSV-2)。此外，我们将识别分泌的效应器 使单核细胞对病毒感染敏感的人滋养层细胞，并确定这些因素是否作用于 其他致畸病毒和其他免疫细胞群 我们已经确定了胎盘对病毒感染的可传播抵抗力的新途径，并增强了 对病毒感染的敏感性。在破译构成这些途径的潜在机制时，我们 可能阐明滋养层细胞抵抗病毒的基础，并识别可能特别是 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 旨在减轻和/或预防病毒感染的治疗方法，从而减轻与感染相关的负担 母婴发病率和死亡率。