Topological Mapping of Immune, Microbiota, Metabolomic and Clinical Phenotypes to Reveal ME/CFS Disease Mechanisms - Basic Research Project

项目总结基础研究项目 我们在这个项目中的目标是研究ME/CFS微生物群的分子机制 与免疫系统相互作用导致疾病。免疫激活的异常可能是关键 影响ME/CFS疾病严重程度的因素。然而，我们不知道这些异常在多大程度上：1) 微生物起源，即由ME/CFS患者的微生物失调引起；2)由产生的代谢物引起 由影响免疫或代谢病理生理的微生物群引起；或3)由遗传或 环境因素对ME/CFS患者免疫敏感性的影响因此，迫切需要确定 在ME/CFS中驱动异常免疫激活的免疫细胞、细菌和分子途径。在这里，我们 将通过补充管道询问从ME/CFS患者身上采集的微生物和免疫细胞， 每一个都被设计成隔离微生物免疫轴的一侧。微生物管道将比较ME/CFS- 使用一套相关的免疫分析方法，从患者身上收集相关细菌，从健康对照身上收集细菌。 免疫管道将比较从ME/CFS患者收集的免疫细胞和健康的免疫细胞， 暴露在微生物触发物和免疫细胞激活剂的电池中。总而言之，这些管道将精确定位 通过分子分辨，特定的免疫介导性疾病触发独特的或显著丰富的 ME/CFS条件。我们希望确定微生物和免疫细胞对 观察这些患者的免疫病理变化。我们还希望确定ME/CFS相关的肠道微生物如何 影响免疫系统的不同部分，并确定免疫调节代谢物库 这是这些互动的基础。这项研究项目与临床项目高度协同，因为 他们将共同建立ME/CFS疾病严重性的微生物和免疫相关性，并建立一个框架 疾病机制。该项目还将通过以下方式促进《儿童权利公约》的目标： 微生物和免疫细胞和分子机制，识别潜在的新治疗靶点 具有特征的作用机制，并识别潜在的微生物或转录触发因素； 生物标志物和风险因素。我们的具体目标是：1)鉴定具有免疫调节功能的细菌菌株 可能作为免疫病理学基础的ME/CFS患者(微生物管道)；以及2)确定 基于转录转录询问和表观遗传学的ME/CFS患者免疫细胞对微生物调节剂的作用 州(免疫管道)。影响：通过探测ME/CFS患者对微生物刺激的免疫反应， 我们将确定ME/CFS相关肠道微生物介导免疫激活的分子机制。 这项工作也将为合理发现针对微生物免疫的疗法奠定基础。 用于ME/CFS治疗的工程益生菌的相互作用和发展。

PROJECT SUMMARY BASIC RESEARCH PROJECT Our goal in this project is to investigate the molecular mechanisms by which the ME/CFS microbiome interacts with the immune system to cause disease. Abnormalities in immune activation are likely key contributors to ME/CFS disease severity. However, we do not know to what extent these abnormalities are: 1) microbial in origin, i.e., caused by microbial dysbiosis in ME/CFS patients; 2) caused by metabolites produced by microbiota that influence the immunological or metabolic pathophysiology; or 3) caused by genetic or environmental perturbation of immune sensitivity in ME/CFS patients. There is thus a strong need to identify the immune cells, bacteria, and molecular pathways that drive abnormal immune activation in ME/CFS. Here, we will interrogate microbes and immune cells harvested from ME/CFS patients through complementary pipelines, each designed to isolate one side of the microbe-immune axis. The microbial pipeline will compare ME/CFS- related bacteria collected from patients to bacteria from healthy controls using a set of relevant immune assays. The immune pipeline will compare immune cells collected from ME/CFS patients to healthy immune cells, exposing both to a battery of microbial triggers and immune cell activators. Together, these pipelines will pinpoint with molecular resolution the specific immune-mediated disease triggers unique to or significantly enriched in the ME/CFS condition. We expect to determine the relative contributions of microbes and immune cells toward the immune pathology observed in these patients. We also expect to identify how ME/CFS-related gut microbes impact different compartments of the immune system and to identify the immunomodulatory metabolite repertoire that underlies these interactions. This research project is highly synergistic with the clinical project, in that together they will establish microbial and immune correlates of ME/CFS disease severity and a framework for disease mechanisms. This project will also contribute to the goals of the CRC through: characterization of microbial and immune cellular and molecular mechanisms, identification of potential new therapeutic targets with characterized mechanism of action, and identification of potential microbial or transcriptional triggers, biomarkers, and risk factors. Our Specific Aims are: 1) To identify immunomodulatory bacterial strains from ME/CFS patients that may underlie immunopathology (Microbial Pipeline); and 2) To determine the response of ME/CFS patient immune cells to microbial modulators based on transcriptomic interrogation and epigenetic states (Immune Pipeline). Impact: By probing the immune responses of ME/CFS patients to microbial stimuli, we will define the molecular mechanisms by which ME/CFS-related gut microbes mediate immune activation. This work will also lay the foundation for rational discovery of therapeutics that target microbe-immune interactions, and development of engineered probiotics for ME/CFS treatment.