Mechanisms of trophoblast-induced immune modulation

滋养层诱导的免疫调节机制

• 批准号: 10461038
• 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/10461038
• 关键词: Animal Model; Bacteria; Cells; Characteristics; Cre lox recombination system; 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; 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.

本申请是为了响应 RFA：AI-18-023“母胎界面的免疫机制”。 滋养层是囊胚和母体蜕膜之间的第一个接触点，具有 在塑造植入部位的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）充当周围环境的“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和 受损的组织。众所周知，I 型干扰素的产生是多个物种胎盘的一个特征， 包括人类； IFNβ 是主要类型，尤其是在妊娠早期。在这样的背景下 怀孕时，我们已经证明胎盘中 IFNβ 信号传导的丧失会导致：1) 病毒复制失控 和胎儿病毒感染，2) 孕产妇死亡率和 3) 对细菌产品过敏；建议批评 IFNβ信号在保护妊娠中的作用。我们的中心假设是胎盘 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，因为它能够 调节 TLR 的反应可以作为植入部位的主要免疫调节因子。 该提议的前提是，在滋养层中，TLR2/4 和 TLR2/4 之间存在内在的串扰。 IFNβ 途径可提供针对感染的保护，同时还可防止潜在的有害亲 通过抑制 NF-κB 调节的炎症细胞因子的转录来调节炎症反应。此外，我们 已经确定了涉及 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 这些途径的组成部分用于微生物免疫逃避的目的。病原体（例如病毒）可能会 抑制 IFNβ 并增强病毒复制所需的炎症；或细菌/寄生虫可能促进 IFNβ 表达抑制细胞感染的 NFκB 炎症。我们的具体目标是： 目标 1. 确定 IFNβ 如何与 Axl 相互作用来调节滋养层炎症。 目标 2. 表征 IFN 和 TAM 调节 NF-κB- 转录的机制 滋养层中的依赖基因。 目标 3. 确定病毒感染对动物体内 Axl-IFNβ-TLR2/4 之间串扰的影响 模型。 完成这些目标后，我们将更好地了解 IFNβ 和 I 型的重要作用 怀孕期间宿主对微生物感染反应中的干扰素受体信号传导。我们将阐明 IFNβ、 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，还可以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增强我们的 了解母体/胎儿界面免疫调节的复杂性，也将提供 通过调节来识别预测标记和新治疗方法的新机会 IFNβ/TAM 受体信号传导可保护处于病毒感染风险或大流行期间的孕妇。