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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：
9978714
负责人：
Carolyn B Coyne
金额：
$ 68.84万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978714
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

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.

本应用程序的首要目标是确定人胎盘先天免疫途径和因素