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: 10540679
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540679
• 关键词: Affect; 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; Viral Physiology; 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; interferon-alpha B; 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儿来源的 胎盘、母体蜕膜和病毒感染。这种免疫平衡促进了半人的耐受性 保护同种异体胎儿免受母体病原体侵袭。寨卡病毒是一种由蚊子传播的黄病毒。 在为数不多的能够跨越物理和免疫屏障的微生物(称为TORCH病原体)中 以感染发育中的胎儿。然而，ZIKV和其他火炬的机制 病原体克服了母胎界面的保护性抗病毒反应，人们对此知之甚少。 干扰素-λ是一种细胞因子，在解剖屏障上有助于抗病毒免疫，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感染已证明干扰素-λ在胎盘屏障的抗病毒免疫中起作用。 然而，我们发现，在先天性ZIKV期间，干扰素-λ也可以诱导胎儿和胎盘的病理改变。 感染，这是母体组织中干扰素-λ信号转导的结果。此外，我们发现， 当代亚洲血统的ZIKV毒株在诱导干扰素-λ依赖性病理的能力上有所不同。此属性 与未怀孕的小鼠对干扰素-γ的敏感性增强以及观察到的疾病的严重程度相对应 在先天性ZIKV感染的非人类灵长类动物模型中。我们推测ZIKV毒株特异性的干扰素-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 回应。干扰素-λ信号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，以及相关的自身免疫性疾病 干扰素水平升高，妊娠结局不佳。我们将定义干扰素-λ特异性的抗病毒反应 在小鼠、胎盘细胞系和原代人类滋养层细胞中。我们将确定ZIKV是否能够更好地 与其他黄病毒相比，拮抗这种反应，以及TORCH病原体，如ZIKV和 RUBV在胎盘中具有拮抗干扰素-λ介导的免疫的能力。我们将使用一个小鼠模型 母系干扰素-λ信号诱导的先天性寨卡病毒感染的病理免疫反应特征 并生成条件性基因敲除行来定义调节该反应的细胞类型。我们将使用反转 遗传学方法来定义病毒致病的决定因素，特别是对平衡的作用 病毒E蛋白第三结构域的多态。

项目成果

Structurally Conserved Domains between Flavivirus and Alphavirus Fusion Glycoproteins Contribute to Replication and Infectious-Virion Production.

黄病毒和甲病毒融合糖蛋白之间的结构保守域有助于复制和感染性病毒颗粒的产生。

• DOI: 10.1128/jvi.01774-21
• 发表时间: 2022
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Rangel,MargaritaV;Catanzaro,Nicholas;Thannickal,SaraA;Crotty,KellyA;Noval,MariaG;Johnson,KatherineEE;Ghedin,Elodie;Lazear,HelenM;Stapleford,KennethA
• 通讯作者: Stapleford,KennethA