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.

抽象的母胎界面的抗病毒免疫涉及胎儿源性病毒之间的三向相互作用胎盘、母体蜕膜和病毒感染的这种免疫平衡促进了半子宫的耐受性。同种异体胎儿，同时保护其免受母体病原体寨卡病毒（ZIKV）（一种蚊媒黄病毒）的侵害。少数能够克服物理和免疫屏障的微生物（称为 TORCH 病原体）然而，ZIKV 和其他 TORCH 的机制。病原体如何克服母胎界面的保护性抗病毒反应尚不清楚。干扰素 lambda (IFN-λ) 是一种细胞因子，有助于在解剖屏障处产生抗病毒免疫，包括胎盘。对原代人胎盘滋养层、人胎盘外植体和小鼠模型的研究先天性 ZIKV 感染已证明 IFN-λ 在胎盘屏障的抗病毒免疫中发挥作用。然而，我们发现 IFN-λ 也可以在先天性 ZIKV 期间诱发胎儿和胎盘病理学感染，这是母体组织中 IFN-λ 信号传导的结果。此外，我们发现。当代亚洲谱系 ZIKV 毒株诱导 IFN-λ 依赖性病理的能力有所不同。对应于非怀孕小鼠对 IFN-γ 的敏感性增强，以及观察到的疾病的严重程度我们在先天性 ZIKV 感染的非人灵长类动物模型中捕获了 ZIKV 毒株特异性 IFN-λ。反应调节胎盘中的保护性抗病毒反应和病理性母体免疫 IFN-λ 信号传导的保护作用和病理作用之间的平衡对于调节反应非常重要。控制 TORCH 病原体，例如 ZIKV 和风疹病毒，以及相关的自身免疫性疾病 IFN 产量升高和妊娠结局不佳，我们将定义 IFN-λ 特异性抗病毒反应。我们将确定 ZIKV 是否能够更好地在小鼠、胎盘细胞系和原代人类滋养层细胞中发挥作用。与其他黄病毒相比，TORCH 病原体（例如 ZIKV 和 RUBV，具有拮抗胎盘中 IFN-λ 介导的免疫的能力，我们将使用 RUBV 的小鼠模型。先天性 ZIKV 感染来表征母体 IFN-λ 信号引发的病理免疫反应并生成条件敲除系来定义介导这种反应的细胞类型。遗传学方法来定义发病机制的病毒决定因素，特别是平衡的作用病毒E蛋白结构域III的多态性。