Mechanisms of trophoblast-induced immune modulation

这项申请是对RFA：AI-18-023“母胎界面的免疫机制”的响应。 滋养层细胞代表胚泡和母体蜕膜之间的第一个接触点，具有 在形成植入部位的免疫环境方面发挥积极作用。滋养层细胞表达模式 识别受体(PRR)，起到周围环境“传感器”的作用。通过这些 受体，滋养层细胞可以识别细菌、病毒和其他微生物以及濒临死亡的细胞和 受损的组织。已知I型干扰素的产生是几个物种胎盘的特征， 包括人类；干扰素β是主要的类别，特别是在怀孕的前三个月。在…的背景下 在妊娠期间，我们发现在胎盘中失去干扰素β信号会导致：1)病毒复制失控 和胎儿病毒感染，2)产妇死亡率和3)对细菌产品的过敏性； 干扰素β信号在妊娠保护中的作用我们的中心假设是胎盘干扰素β信号 对于在病毒感染期间保护胎儿和母亲至关重要，因为它有能力 调节TLRs的反应可以作为植入部位的主要免疫调节因子。 这一提议的前提是，在滋养层细胞中，TLR2/4和TLR2/4之间存在内在的串扰 干扰素β途径，提供对感染的保护，但也防止潜在的有害前 通过抑制核因子-κB转录调控的炎症反应。此外，我们 发现了一种涉及受体的滋养细胞免疫调节新机制， 尤其是Axl受体。这些发现的意义在于我们的前提是病原体可能劫持 这些途径的组成部分，用于微生物免疫逃避。病原体，如病毒，可能 抑制干扰素β并增强病毒复制所需的炎症；否则细菌/寄生虫可能会促进干扰素β 表达抑制细胞感染的核因子κB-炎症。我们的具体目标是： 目的1.确定干扰素β与AXL相互作用对滋养层细胞炎症的调节作用。 目的2.研究干扰素和TAMs对核因子-κB-1转录的调控机制。 滋养层细胞中的依赖基因。 目的3.明确病毒感染对AX1-干扰素β-TLR2/4在动物体内的串扰的影响 模特们。 完成这些目标后，我们将对干扰素β和I型干扰素的基本作用有更好的理解。 妊娠期间宿主对微生物感染反应中的干扰素受体信号。我们将阐明干扰素β是如何， 它的调控途径，如受体，不仅保护胎儿免受病毒感染，而且还 防止有害的炎症反应。这些研究的结果不仅将加强我们的 了解母体/胎儿界面免疫调节的复杂性，也将提供 识别预测标志物的新机会和通过调节的新的治疗方法 干扰素β/受体信号转导，以保护有病毒感染风险或流行期间的孕妇。

This application is in response to the RFA: AI-18-023 “Immune Mechanisms at the Maternal-Fetal Interface”. The trophoblast represents the first point of contact between the blastocyst and the maternal decidua and has an active role in shaping the immunological milieu at the implantation site. Trophoblast cells express pattern recognition receptors (PRR) that function as “sensors” of the surrounding environment. Through these receptors, the trophoblast can recognize bacteria, viruses, and other microbes as well as dying cells and damaged tissue. Type I IFN production is known to be a characteristic of the placenta in several species, including humans; and IFNβ is the predominant class, especially during the first trimester. In the context of pregnancy, we have shown that loss of IFNβ signaling in the placenta leads to: 1) uncontrolled viral replication and fetal viral infection, 2) maternal mortality and 3) hypersensitivity to bacterial products; suggesting a critical role of IFNβ signaling in the protection of pregnancy. Our central hypothesis is that placental IFNβ signaling is critical for the protection of the fetus and the mother during viral infections and because its ability to modulate TLRs’ responses can function as a major immune modulatory factor at the implantation site. The premise for this proposal is that in the trophoblast, there is an intrinsic cross talk between TLR2/4 and IFNβ pathway that provides protection against infection, but also prevents potential detrimental pro- inflammatory responses by inhibiting transcription of NF-κB regulated inflammatory cytokines. In addition, we have identified a novel mechanism of immune regulation in the trophoblast involving the TAM receptors, specifically the Axl receptor. The significance of these findings is in our premise that pathogens might hijack components of these pathways for purposes of microbial immune evasion. Pathogens such as viruses might inhibit IFNβ and enhance inflammation necessary for viral replication; or bacteria/parasites might promote IFNβ expression to inhibit NFκB-inflammation for cell infection. Our specific aims are: Aim 1. Determine how IFNβ interacts with Axl to regulate trophoblast inflammation. Aim 2. To characterize the mechanism by which IFNs and TAMs regulate transcription of NF-κB- dependent genes in the trophoblast. Aim 3. Define the impact of viral infections on the cross talk between Axl-IFNβ-TLR2/4 in animal models. Upon completion of these aims we will have a better understanding of the essential role for IFNβ and type I IFN receptor signaling in host responses to microbial infections during pregnancy. We will elucidate how IFNβ, and its regulatory pathways, such as TAM receptors, protect the fetus not only against viral infections but also prevents detrimental inflammatory responses. The outcome of these studies not only will enhance our understanding of the complexity of immune regulation at the maternal/fetal interface but also will provides novel opportunities for the identification of predictive markers and new therapeutic approaches by modulating IFNβ/TAM receptor signaling to protect pregnant women at risk to viral infections or during pandemics.