The role of Interferon lambda signaling in flavivirus transmission and pathogenesis at the maternal-fetal interface

干扰素 lambda 信号传导在黄病毒传播和母胎界面发病机制中的作用

基本信息

批准号：
10312708
负责人：
Helen Lazear
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312708
关键词：
Affect Allogenic Americas Anatomy Antiviral Response Asian Atrophic Autoimmune Diseases Blocking Antibodies Cell Line Cells Congenital Abnormality Data Decidua Dengue Virus Disease E protein Equilibrium Exhibits Fetal Development Fetal Growth Retardation Fetus Flavivirus Gene Expression Profile Genetic Determinism Genetic Polymorphism Genetic Transcription Histology Human Immune Immune response Immunity Immunologics Impairment Interferon Type II Interferons Knock-out Knockout Mice Maternal-Fetal Exchange Mediating Microbe Modeling Molecular Virology Mus Neurodevelopmental Disorder Outcome Pathogenesis Pathogenicity Pathologic Pathology Phenotype Placenta Placental Insufficiency Pregnancy Pregnancy Outcome Production Property Resistance Role Rubella virus Severity of illness Side Signal Transduction Systemic infection Teratogens Testing Tissues Viral Virulent Virus Diseases West Nile virus ZIKV infection Zika Virus antiviral immunity cell type clinically relevant conditional knockout congenital zika syndrome cytokine fetal fetal infection genetic approach immune activation mosquito-borne mouse model nerve stem cell nonhuman primate pathogen prevent programs receptor response reverse genetics transmission process trophoblast virus genetics

项目摘要

ABSTRACT Antiviral immunity at the maternal-fetal interface involves a three-way interaction between the fetal-derived placenta, the maternal decidua, and viral infection. This immunological balance promotes tolerance of the semi- allogeneic fetus while protecting it from maternal pathogens. Zika virus (ZIKV), a mosquito-borne flavivirus, is among the few microbes (termed TORCH pathogens) able to surmount the physical and immunological barrier of the placenta to infect the developing fetus. However, the mechanisms by which ZIKV and other TORCH pathogens overcome the protective antiviral response at the maternal-fetal interface are poorly understood. Interferon lambda (IFN-λ) is a cytokine that contributes to antiviral immunity at anatomic barriers, including the placenta. Studies with primary human placental trophoblasts, human placental explants, and mouse models of congenital ZIKV infection have demonstrated a role for IFN-λ in antiviral immunity at the placental barrier. However, we have found that IFN-λ also can induce fetal and placental pathology during congenital ZIKV infection, an effect that results from IFN-λ signaling in maternal tissues. Furthermore, we found that contemporary Asian-lineage ZIKV strains differ in their ability to induce IFN-λ-dependent pathology. This property corresponds to enhanced sensitivity to IFN-γ in non-pregnant mice, as well as to the severity of disease observed in non-human primate models of congenital ZIKV infection. We hypothesize that ZIKV strain-specific IFN-λ responses regulate both protective antiviral responses in the placenta and pathologic maternal immune responses. The balance between the protective and pathologic effects of IFN-λ signaling is important for controlling TORCH pathogens such as ZIKV and rubella virus, as well as for autoimmune conditions associated with elevated IFN production and poor pregnancy outcomes. We will define the IFN-λ specific antiviral response in mice, placental cell lines, and primary human trophoblasts. We will determine whether ZIKV is better able to antagonize this response compared to other flaviviruses and whether TORCH pathogens, such as ZIKV and RUBV, share an ability to antagonize IFN-λ-mediated immunity in the placenta. We will use a mouse model of congenital ZIKV infection to characterize the pathologic immune response elicited by maternal IFN-λ signaling and generate conditional knockout lines to define the cell types that mediate this response. We will use reverse genetics approaches to define the viral determinants of pathogenesis, particularly a role for a balanced polymorphism in domain III of the viral E protein.

抽象的母体狂热界面处的抗病毒药免疫涉及胎儿衍生的三向相互作用胎盘，母体Decidua和病毒感染。这种免疫平衡促进了半耐受性同种异体胎儿在保护其免受母体病原体的侵害时。 Zika病毒（Zikv），一种蚊子传播的黄病毒，是在少数微生物（称为火炬病原体）中，可以掩盖物理和免疫障碍胎盘感染发育中的胎儿。但是，ZIKV和其他火炬的机制病原体克服了母体界面处受保护的抗病毒反应的了解很少。干扰素lambda（IFN-λ）是一种细胞因子，在解剖屏障时有助于抗病毒免疫，包括胎盘。针对原发性人体占地滋养细胞，人体占位epplant和小鼠模型的研究先天性ZIKV感染已表现出在位置屏障的抗病毒免疫中IFN-λ的作用。但是，我们发现IFN-λ还可以在先天性ZIKV期间诱导胎儿和占地病理感染，这是由IFN-λ信号在材料组织中产生的作用。此外，我们发现当代亚洲ZIKV的ZIKV菌株在诱导IFN-λ依赖性病理学的能力上有所不同。这个属性对应于非怀孕小鼠对IFN-γ的敏感性，以及观察到的疾病严重程度在非人类ZIKV感染的非人类私人模型中。我们假设ZIKV菌株特异性IFN-λ 反应调节了零食中受保护的抗病毒反应和病理材料免疫回答。 IFN-λ信号的受保护和病理效应之间的平衡对于控制火炬病原体，例如ZIKV和Rubella病毒，以及与自身免疫性有关 IFN产生升高和妊娠结局不佳。我们将定义IFN-λ特异性抗病毒反应在小鼠中，斑点细胞系和原代人滋养细胞。我们将确定ZIKV是否能够更好与其他黄病毒相比，对此反应以及火炬病原体（例如ZIKV和 RUBV，具有拮抗IFN-λ介导的免疫力的能力。我们将使用鼠标模型先天性ZIKV感染以表征由生物IFN-λ信号引起的病理免疫反应并生成条件敲除线以定义介导此响应的细胞类型。我们将使用反向遗传学方法来定义发病机理的病毒决定剂，尤其是平衡的作用病毒E蛋白的结构域III中的多态性。