The IRF-type I interferon system during gestation

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 获得性免疫反应。在我们对以下过程的理解方面取得了实质性进展 导致I型干扰素(=干扰素α/β)通过红外线产生，并由它们通过 STAT蛋白。尽管干扰素α/β、RFs和STATs已经在病原体的背景下被广泛研究 在成年生物体中的反应，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。 未被开发的。例如，尽管干扰素在几十年前就被发现了，但仍然不清楚 它们穿过所谓的血-胎盘屏障，即发育中的胎儿在什么时候能够对 病原体与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 与病原体相关的出生缺陷。事实上，许多通过围产期传播的病原体(如巨细胞病毒、风疹、 LCMV，最近的寨卡病毒)被认为会导致先天性出生缺陷，然而，目前还不清楚 无论是病原体本身，还是由此产生的免疫反应，都是造成发育缺陷的原因。 我们构思的一种新的报告小鼠品系允许可视化干扰素α/β相遇并提供 干扰素反应的时间整合图。干扰素α或干扰素β基因座的其他报告敲入菌株 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老鼠来 缺乏干扰素系统成分的动物研究干扰素的诱导、传播和影响 妊娠不同阶段的干扰素。PolyI：C模拟dsrna从而感染病毒，是一种有效的 干扰素α/β诱导剂。在目标1中，我们将研究干扰素α/β在注射后是否在胎儿中引起反应 患有PolyI：C的母体动物来自胎儿本身，或已通过 来自母体一侧的胎盘。相反，我们将测试干扰素α/β是否可能从胎儿传递到 母体动物的血液流动。淋巴细胞性脉络膜脑膜炎病毒(LCMV)在实验室中经常使用 研究更危险的相关病毒(艾滋病毒、丙型肝炎病毒、乙肝病毒，现在是寨卡病毒)的持续感染，以及 导致类似寨卡病毒的严重出生缺陷。在小鼠体内，LCMV在系统内迅速传播，通过 围产期强烈诱导型干扰素的产生。干扰素α/β受体缺陷小鼠 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记者 小鼠品系，并设计杂交，以使只有母体动物或只有胎儿是IRF 和/或干扰素α/β受体缺陷，以监测I型干扰素的产生、反应和病毒载量 感染。我们期望拟议的研究将大大扩展我们对以下贡献的理解 IRFS和I型干扰素对妊娠期存在的独特免疫环境产生了影响。

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.