Control of influenza virus induced type I interferon signaling during pregnancy

项目摘要/摘要 在怀孕期间，感染性侮辱是很常见的；在怀孕九个月期间，大约60%的孕妇 自我报告至少一种疾病，最常见的是病毒性上呼吸道(URT)感染。 尽管URT营养病毒在呼吸道上皮细胞中复制，但诱导的炎症细胞因子如 I型干扰素在全身循环，可进入胎盘。最近的研究表明，病毒 诱导型IFN可能是对胎儿发育产生不利影响的主要驱动因素。城市轨道交通感染期间 然而，怀孕通常与出生缺陷或流产无关。因此，原因尚不清楚 母亲感染一种病原体，如流感病毒，也会导致胎儿接触干扰素，但不会 损害胎儿健康。我们假设，一种未知的干扰素调控途径是 这种明显的差异。通过进行全基因组CRISPR/Cas筛查，我们鉴定出一种G蛋白 依赖偶联雌激素受体1(GPER1)的信号通路保护胎儿健康免受I型干扰素的影响 母体甲型流感病毒(IAV)感染期间的信号转导。这一途径的中断导致胎儿表型 与由直接先天性感染引起的疾病一样严重。重要的是，这条途径的活性是 仅限于生殖和胎儿组织；其活性的变化对母体没有可测量的影响。 在IAV感染期间的健康状况。本应用程序的主要目标是了解GPER1介导的信令 通常保护胎儿健康不受炎症性母体细胞因子如I型干扰素的影响。在目标1中，我们将定义 GPER1诱导的GPCR信号如何抑制干扰素诱导的JAK/STAT信号和干扰素刺激 基因表达。这些实验将定义一种以前未知的干扰素信号控制机制。 在目标2中，我们将确定何时何地需要GPER1信号来保护胎儿健康，以及 GPER1基因异常对体内和原代人胎盘器官细胞生理学的影响 文化。这些实验将允许对母体炎症如何妥协的基本机制的深入了解 胎儿发育。最后，在目标3中，我们将探索干扰素信号对胎盘的影响 当GPER1缺失时的结构/功能，并评估过度激活GPER1信号的潜力 在通常会损害胎儿发育的炎症条件下。总而言之，这些研究不仅将 允许更全面地了解干扰素的调节机制和胎儿/母体免疫 反应，但也可以作为最终一流治疗的基础，旨在保护胎儿 在不影响母体免疫力的情况下预防炎症。

PROJECT SUMMARY/ABSTRACT Infectious insults are common during pregnancy; over the nine months of gestation ~60% of pregnant women self-report at least one illness, with viral upper respiratory tract (URT) infections being the most common. Although URT-trophic viruses replicate in the respiratory epithelium, the induced inflammatory cytokines like type I interferon (IFN) circulate systemically and can access the placenta. Recent work has shown that virally induced type I IFNs can be major drivers of adverse effects on fetal development. URT infections during pregnancy, however, are not typically linked to birth defects or miscarriage. It was therefore unclear why maternal infection with a pathogen like an influenza virus, which also induces to fetal IFN exposure, would not compromise fetal health. We hypothesized that an uncharacterized IFN regulatory pathway was the answer to this apparent discrepancy. By performing a genome-wide CRISPR/Cas screen, we identified a G-protein coupled estrogen receptor 1 (GPER1) dependent signaling pathway that protected fetal health from type I IFN signaling during maternal influenza A virus (IAV) infection. Disruption of this pathway led to fetal phenotypes as severe as those caused by direct congenital infections. Importantly, the activities of this pathway were restricted to reproductive and fetal tissues; alterations of its activity had no measurable effect on maternal health during IAV infection. The major goal of this application is to understand how GPER1-mediated signaling normally protects fetal health from inflammatory maternal cytokines such as type I IFN. In aim 1, we will define how GPER1-induced GPCR signaling suppresses IFN-induced JAK/STAT signaling and interferon-stimulated gene expression. These experiments will define a previously unknown mechanism for control of IFN signaling. In aim 2, we will characterize where and when GPER1 signaling is required to protect fetal health, as well as the effects of GPER1 dysregulation on cell physiology both in vivo and in primary human placental organoid cultures. These experiments will allow basic mechanistic insights into how maternal inflammation compromises fetal development. Finally, in aim 3, we will explore the consequences of IFN signaling on placental structure/function when GPER1 is absent and also evaluate the potential of hyper-activating GPER1 signaling under the inflammatory conditions that normally harm fetal development. Together, these studies will not only allow for a more complete understanding of IFN regulatory mechanisms and the fetal/maternal immune response but could also serve as the basis for an eventual first-in-class treatment designed to protect the fetus from inflammation without compromising maternal immunity.