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

• 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
• 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

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.

摘要 母胎界面的抗病毒免疫涉及胎源性抗体和胎源性抗体之间的三向相互作用。 胎盘、母体蜕膜和病毒感染。这种免疫平衡促进了半- 同种异体胎儿，同时保护其免受母体病原体的侵害。寨卡病毒（ZIKV）是一种蚊媒黄病毒， 在少数微生物（称为TORCH病原体）中， 感染发育中的胎儿然而，ZIKV和其他TORCH 病原体克服母胎界面的保护性抗病毒反应的机制知之甚少。 干扰素λ（IFN-λ）是一种细胞因子，其有助于在解剖屏障处的抗病毒免疫，所述解剖屏障包括： 胎盘原代人胎盘滋养层细胞、人胎盘外植体和小鼠模型的研究 先天性ZIKV感染已经证明了IFN-λ在胎盘屏障处的抗病毒免疫中的作用。 然而，我们已经发现IFN-λ也可以在先天性ZIKV期间诱导胎儿和胎盘病理学， 感染，一种由母体组织中的IFN-λ信号传导引起的效应。此外，我们发现， 当代亚洲谱系ZIKV毒株在它们诱导IFN-λ依赖性病理学的能力方面不同。此属性 对应于非妊娠小鼠对IFN-γ的敏感性增强，以及观察到的疾病严重程度 在先天性ZIKV感染的非人灵长类动物模型中。我们假设ZIKV株特异性IFN-λ 免疫应答调节胎盘中的保护性抗病毒应答和病理性母体免疫 应答IFN-λ信号传导的保护作用和病理作用之间的平衡对于 控制TORCH病原体，如ZIKV和风疹病毒，以及与自身免疫性疾病相关的 干扰素分泌增多，妊娠结局不佳我们将定义IFN-λ特异性抗病毒反应 在小鼠、胎盘细胞系和原代人滋养层中。我们将确定ZIKV是否能够更好地 与其他黄病毒相比，TORCH病原体（如ZIKV和ZIKV）是否拮抗这种应答， RUBV具有拮抗胎盘中IFN-λ介导的免疫的能力。我们将使用一个小鼠模型， 先天性ZIKV感染以表征由母体IFN-λ信号传导引起的病理性免疫应答 并产生条件性敲除细胞系以确定介导这种反应的细胞类型。我们将使用反向 遗传学方法来定义致病的病毒决定因素，特别是平衡的作用， 在病毒E蛋白的结构域III中的多态性。