Mechanisms of trophoblast-induced immune modulation

本申请是对RFA：AI-18 - 023“母胎界面的免疫机制”的回应。 滋养层是胚泡和母体蜕膜之间的第一个接触点， 在植入部位形成免疫环境中发挥积极作用。滋养层细胞表达模式 识别受体（PRR）作为周围环境的“传感器”。通过这些 受体，滋养层可以识别细菌，病毒和其他微生物以及垂死的细胞， 受损组织已知I型IFN的产生是几个物种胎盘的特征， 包括人类; IFN β是主要的类别，尤其是在妊娠早期。背景下 在妊娠期间，我们发现胎盘中IFN β信号的丢失导致：1）病毒复制失控 和胎儿病毒感染，2）孕产妇死亡率和3）对细菌产品的超敏反应;这表明一个关键的 IFN β信号在妊娠保护中的作用。我们的中心假设是胎盘IFN β信号 对于在病毒感染期间保护胎儿和母亲至关重要， 调节TLR应答的免疫调节因子可以在植入部位起主要免疫调节因子的作用。 该建议的前提是，在滋养层中，TLR 2/4和TLR 2/4之间存在内在的串扰。 IFN β通路，提供抗感染保护，但也防止潜在的有害前体， 通过抑制NF-κ B调节的炎性细胞因子的转录来调节炎症反应。另外我们 已经确定了一种涉及TAM受体的滋养层免疫调节的新机制， 特别是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 这些途径的组分用于微生物免疫逃避的目的。病毒等病原体可能 抑制IFN β并增强病毒复制所必需的炎症;或细菌/寄生虫可能促进IFN β 表达以抑制NF κ B-炎症细胞感染。我们的具体目标是： 目标1。确定IFN β如何与Axl相互作用以调节滋养层炎症。 目标二。为了阐明IFN和TAM调节NF-κ B B-1转录的机制， 滋养层中的依赖基因。 目标3：定义病毒感染对动物中Axl-IFN β-TLR2/4之间的串扰的影响 模型 在完成这些目标后，我们将更好地了解IFN β和I型干扰素的重要作用。 IFN受体信号在妊娠期间对微生物感染的宿主反应中的作用。我们将阐明IFN β， 及其调节途径，如TAM受体，不仅保护胎儿免受病毒感染， 防止有害的炎症反应。这些研究的结果不仅将提高我们的 了解母亲/胎儿界面免疫调节的复杂性， 通过调节细胞因子的表达， IFN β/TAM受体信号传导保护处于病毒感染风险或在大流行期间的孕妇。

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.