The IRF-type I interferon system during gestation

妊娠期间的 IRF-I 型干扰素系统

• 批准号: 9300592
• 负责人: MICHAEL DAVID
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300592
• 关键词: Adult; Animals; Apoptosis; Area; Biological; Blood; Blood Circulation; Cause of Death; Cells; Child; Clinical; Congenital Abnormality; Cytomegalovirus; Dangerousness; Decidua Basalis; Development; Developmental Process; Double-Stranded RNA; Elements; Environment; Family member; Fetus; Gene Activation; General Population; HIV; HIV/HCV; Hepatitis B; IRF3 gene; Imagery; Immune; Immune response; Immunologics; Individual; Infection; Inflammatory; Influenza; Injection of therapeutic agent; Innate Immune Response; Interferon Type I; Interferon Type II; Interferon-alpha; Interferons; Investigation; Knock-in; Lead; Lymphocytic choriomeningitis virus; Mediating; Mediator of activation protein; Microcephaly; Monitor; Mouse Strains; Mus; Neurologic; Organism; Perinatal; Perinatal Infection; Physiological; Placenta; Poly I-C; Pregnancy; Process; Production; Proteins; RNA Viruses; Reporter; Role; Rubella; STAT protein; STAT1 gene; Septic Shock; Shapes; Side; Signal Transduction; Syndrome; System; TLR3 gene; Testing; Time; Transcriptional Activation; Viral Load result; Virus; Virus Diseases; Zika Virus; cytokine; design; experimental study; in utero; insight; interest; novel; pathogen; pregnant; receptor; response; transcription factor; transmission process

The innate immune response is an ancient, non antigen-specific defense system made up countermeasures that restrict the replication of pathogens early in infection. A successful innate response promotes the secretion of cytokines, particularly interferons (IFNs), that shape the later pathogen-specific acquired immune response. Substantial progress has been made in our understanding of the processes that lead to the production of type I interferons (=IFNα/β) via IRFs, and the biological responses elicited by them via STAT proteins. Although IFNα/β, IRFs, and STATs have been extensively studied in the context of pathogen responses in adult organisms, their role in infectious processes during gestation has remained largely unexplored. For instance, even though interferons were discovered decades ago, it is still not clear whether they cross the so-called blood-placenta barrier, or at what point a developing fetus is capable of responding to a pathogen encounter with its own production of interferons. Similarly, it is unclear if interferons contribute to pathogen-associated birth defects. Indeed, many perinatally transmitted pathogens (e.g. hCMV, Rubella, LCMV, more recently Zika virus) are known to give rise to congenital birth defects, however, it is unclear whether the pathogen per se, or the resulting immune response is responsible for developmental deficiencies. A novel reporter mouse strain we conceived allows for the visualization of IFNα/β encounters and provides a time-integrated picture of interferon responses. Additional reporter knock-in strains in the IFNα or IFNβ locus permit the monitoring of interferon production. We intend to utilize these mice in the context of crosses to animals lacking components of the interferon system to study the induction, transmission and the effects of interferons at various stages of gestation. PolyI:C, which mimics dsRNA and thus viral infection, is a potent inducer of IFNα/β. In aim 1 we will investigate whether the IFNα/β eliciting responses in the fetus after injection of the maternal animal with PolyI:C is derived from the fetus itself, or has been transmitted through the placenta from the maternal side. Conversely, we will test whether IFNα/β might be passed from the fetus into the bloodstream of the maternal animal. Lymphocytic choriomeningitis virus (LCMV) is frequently used in labs to study persistent infections by more dangerous related viruses (HIV, HCV, HBV, and now Zika virus), and causes severe birth defects similar to Zika virus. In mice, LCMV rapidly spreads systemically, is transmitted perinatally and strongly induces type I interferon production. IFNα/β-receptor (IFNAR)-deficient mice are unable to clear LCMV and develop a persistent viral infection. Thus, in aim 2 we propose to use our reporter mouse strain, and crosses designed such that either only the maternal animal, or only the fetuses are IRF and/or IFNα/β-receptor deficient, to monitor type I interferon production, responses and viral loads during infection. We expect the proposed studies will significantly extend our understanding of the contributions of IRFs and type I interferons to the unique immunological environment that exists during the gestation period.

先天免疫反应是一种古老的、非抗原特异性的防御系统 在感染早期限制病原体复制的对策 成功的先天反应。 促进细胞因子的分泌，特别是干扰素（IFN），形成后来的病原体特异性 我们对获得性免疫反应过程的理解已经取得了实质性进展。 通过 IRF 导致 I 型干扰素 (= IFNα/β) 的产生，并通过它们引起生物反应 尽管 IFNα/β、IRF 和 STAT 已在病原体中得到广泛研究。 虽然成年生物体的反应，但它们在妊娠期间感染过程中的作用在很大程度上仍然存在 例如，尽管几十年前就发现了干扰素，但仍不清楚是否存在。 它们穿过所谓的血胎盘屏障，或者说发育中的胎儿在什么时候能够对 同样，尚不清楚干扰素是否会导致病原体的产生。 事实上，许多围产期传播的病原体（例如 hCMV、风疹、 已知 LCMV（最近的寨卡病毒）会导致先天性出生缺陷，但目前尚不清楚 病原体本身或由此产生的免疫反应是否导致发育缺陷。 我们设想的一种新型报告小鼠品系可以实现 IFNα/β 相遇的可视化，并提供 干扰素反应的时间积分图。 IFNα 或 IFNβ 基因座中的其他报告基因敲入菌株。 我们打算在杂交中利用这些小鼠来监测干扰素的产生。 缺乏干扰素系统成分的动物来研究干扰素的诱导、传播和影响 PolyI:C 可以模拟 dsRNA，从而模拟病毒感染，是一种有效的干扰素。 IFNα/β 诱导剂 在目标 1 中，我们将研究注射后 IFNα/β 是否会在胎儿中引起反应。 携带 PolyI:C 的母体动物来自胎儿本身，或通过胎儿传播 从母体侧取出胎盘，我们将测试IFNα/β是否可以从胎儿传递到体内。 实验室经常使用母体动物的血液。 研究更危险的相关病毒（HIV、HCV、HBV，以及现在的寨卡病毒）的持续感染，以及 与寨卡病毒类似，LCMV 在小鼠体内迅速传播、传播，导致严重出生缺陷。 围产期并强烈诱导 I 型干扰素的产生。 无法清除 LCMV 并发展为持续性病毒感染，因此，在目标 2 中，我们建议使用我们的报告基因。 小鼠品系和杂交设计使得只有母体动物或只有胎儿是IRF 和/或 IFNα/β 受体缺陷，以监测 I 型干扰素的产生、反应和病毒载量 我们预计拟议的研究将显着扩展我们对感染的贡献的理解。 IRF 和 I 型干扰素对妊娠期间存在的独特免疫环境产生影响。