Mechanisms of trophoblast-induced immune modulation

滋养层诱导的免疫调节机制

• 批准号: 10226144
• 负责人: GIL G MOR
• 金额: $ 38.5万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226144
• 关键词: Animal Model; Bacteria; Cells; Characteristics; Data; Decidua; Embryo Transfer; Environment; Feedback; Fetus; First Pregnancy Trimester; Genes; Genetic Transcription; Guidelines; Human; Hypersensitivity; IFNAR1 gene; Immune; Immune Evasion; Immune response; Immunologics; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Knockout Mice; Ligation; Lipopolysaccharides; Maternal Mortality; Maternal-Fetal Exchange; Microbe; Modeling; Mothers; Natural Killer Cells; Nuclear; Outcome Study; Parasites; Pathway interactions; Pattern recognition receptor; Placenta; Pregnancy; Pregnancy Complications; Pregnant Women; Production; Receptor Activation; Receptor Signaling; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Risk; Role; Shapes; Signal Transduction; Site; System; TLR2 gene; TLR4 gene; Testing; Tissues; Virus; Virus Diseases; Virus Replication; blastocyst; cell injury; cytokine; fetal; immunoregulation; implantation; macrophage; microbial; novel; novel therapeutic intervention; pandemic disease; pathogen; predictive marker; prevent; receptor; receptor function; response; sensor; trophoblast; type I interferon receptor

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.

该应用是对RFA的响应：AI-18-023“母体界面处的免疫机制”。 滋养细胞代表胚泡和母体decidua之间的接触点，并且 在植入部位塑造免疫环境中的积极作用。滋养细胞表达图案 识别受体（PRR）充当周围环境的“传感器”。通过这些 接收者，滋养细胞可以识别细菌，病毒和其他微生物，以及垂死的细胞和 损坏的组织。众所周知，I型IFN的产生是多种物种的placeta的特征， 包括人类； IFNβ是主要类别，尤其是在孕期。在 怀孕，我们已经表明，pleceta中IFNβ信号的损失导致：1）不受控制的病毒复制 和胎儿病毒感染，2）孕妇死亡率和3）对细菌产物的超敏反应；提出批判性 IFNβ信号传导在保护妊娠中的作用。我们的中心假设是位置IFNβ信号传导 对于在病毒感染期间保护胎儿和母亲至关重要，因为它的能力 调节TLR的反应可以作为植入部位的主要免疫调节因素。 该提议的前提是，在滋养细胞中，TLR2/4和 IFNβ途径可提供防止感染的保护，但也防止了潜在的有害影响 通过抑制NF-κB调控炎症细胞因子的转录来产生炎症反应。另外，我们 已经确定了在滋养细胞中免疫调节的新机制，涉及TAM受体， 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会劫持 这些途径的成分是出于微生物免疫进化的目的。病毒等病原体可能 抑制IFNβ和病毒复制所需的增强感染；或细菌/寄生虫可能促进IFNβ 表达以抑制NFκB炎症的细胞感染。我们的具体目的是： 目标1。确定IFNβ如何与AXL相互作用以调节滋养细胞炎症。 目的2。表征IFN和TAM调节NF-κB-转录的机制 滋养细胞中的依赖基因。 AIM 3。定义病毒感染对AXL-IFNβ-TLR2/4在动物中的串扰的影响 型号。 完成这些目标后，我们将更好地理解IFNβ和I型的基本作用 怀孕期间对微生物感染的宿主反应中的IFN受体信号传导。我们将阐明IFNβ如何 及其调节途径（例如TAM受体）不仅可以保护胎儿免受病毒感染的侵害 防止有害的炎症反应。这些研究的结果不仅会增强我们的 了解母体/胎儿界面上免疫管制的复杂性，但也将提供 通过调节来识别预测标记和新的治疗方法的新机会 IFNβ/TAM受体信号传导可保护有风险的病毒感染或大流行时期的孕妇。