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 获得性免疫反应我们在理解这些进程方面取得了重大进展， 通过IRF导致I型干扰素（=IFNα/β）的产生，以及通过IRF引起的生物学应答， STAT蛋白。尽管IFNα/β、IRF和STAT在病原体的背景下已经被广泛研究， 在成年生物体中，它们在妊娠期间的感染过程中的作用在很大程度上仍然存在。 未开发的例如，尽管干扰素在几十年前就被发现了，但仍然不清楚是否 它们穿过所谓的血-胎盘屏障，或者在发育中的胎儿能够对 一种病原体与其自身产生的干扰素相遇。同样，目前还不清楚干扰素是否有助于 病原体相关的出生缺陷事实上，许多围产期传播的病原体（例如hCMV，风疹， LCMV，最近的寨卡病毒）已知会导致先天性出生缺陷，然而，目前尚不清楚 无论是病原体本身还是由此产生的免疫反应是发育缺陷的原因。 我们设想的一种新的报告小鼠品系允许IFNα/β相遇的可视化， 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 允许监测干扰素的产生。我们打算在杂交的背景下利用这些小鼠， 缺乏干扰素系统成分的动物，以研究干扰素的诱导、传播和影响。 干扰素在妊娠的各个阶段。PolyI：C模拟dsRNA并因此模拟病毒感染， IFNα/β诱导剂。目的1：研究IFNα/β是否能引起胎儿的免疫应答 母体动物的PolyI：C来自胎儿本身，或已通过 胎盘从母体一侧。相反，我们将测试IFNα/β是否可以从胎儿传递到胎儿。 母体动物的血液循环淋巴细胞性脉络丛脑膜炎病毒（LCMV）是实验室中常用的病毒 研究更危险的相关病毒（HIV、HCV、HBV和现在的寨卡病毒）的持续感染， 导致严重的出生缺陷，类似于寨卡病毒。在小鼠中，LCMV迅速全身传播， 围产期和强烈诱导I型干扰素的生产。IFNα/β-受体（IFNAR）缺陷型小鼠 无法清除LCMV并发生持续性病毒感染。因此，在目标2中，我们建议使用我们的报告器 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、应答和病毒载量， 感染我们希望拟议的研究将大大扩展我们对以下方面贡献的理解： IRFs和I型干扰素对妊娠期存在的独特免疫环境的影响。