Molecular Mechanisms of the Dysregulated Immune Response to Ebola Virus

总体：项目摘要/摘要 拟议的P01计划的中心假设是，埃博拉病毒感染导致细胞类型特异性 转录、转录后和翻译后的改变会产生反作用 免疫细胞的反应，导致失调的免疫反应，这自相矛盾地产生“免疫” 瘫痪“和过度炎症。为了解决这一假设，本文提出了三个研究项目。研究 项目1侧重于转录水平的致病机制，而研究项目2侧重于 转录后事件，研究项目3侧重于翻译后修饰，每个都有贡献 对埃博拉病毒失调的免疫反应。免疫反应失调是大多数 在埃博拉病毒病中观察到的发病机制。 所有项目都需要BSL-4核心(核心B)，它将负责执行人类感染 免疫和非免疫细胞，非人类灵长类动物，以及实验的初始步骤，涉及感染 病毒。重要的是，核心B将提供来自同一实验的每个研究项目的样本 确保每个项目的数据可以直接进行比较的样本-这是本P01的独特功能 程序。蛋白质组学核心(核心C)将负责大规模并行测序和质量 以光谱为基础的研究。生物信息学和建模核心(核心D)是生成工具的关键 用于实验设计，包括对OMICS实验的统计帮助，分析OMICS数据 并将OMICS数据集成到网络中，对感染的各种细胞群体的行为进行建模 EBOV。在核心D中所做的工作将合成一个模型来解释转录、转录后和 单个细胞群体的翻译后反应导致免疫失调。全面的 这一合作努力描绘的图景将彻底改变我们对霍乱免疫发病机制的理解 严重的急性病毒感染(例如，新冠肺炎中出现的免疫失衡)。行政核心(核心A) 将负责战略规划、持续评估以及活动的沟通和协调 根据详细的管理计划，对项目的各个组成部分进行管理。 预期的结果将大大有助于我们了解 针对EBOV感染的免疫发病机制发展提出有效的对策。预期中的 结果将包括：(1)详细了解导致免疫失调的转录机制。 对EBOV的应答，(2)阐明转录后机制在免疫失调中的作用 对EBOV的应答，(3)阐明翻译后机制在免疫失调中的作用 对EBOV的反应，以及(4)对已确定的致病机制及其靶向的实验验证。 拟议的紧密协调和全面的分析以前从未对任何病毒进行过。

OVERALL: PROJECT SUMMARY/ABSTRACT The central hypothesis of the proposed P01 Program is that Ebola virus infection leads to cell-type specific transcriptional, posttranscriptional, and posttranslational alterations that create aberrant counterproductive responses of immune cells, leading to a dysregulated immune response, which paradoxically produces “immune paralysis” and hyperinflammation. To address the hypothesis, three Research Projects are proposed. Research Project 1 focuses on pathogenic mechanisms at the transcriptional level, while Research Project 2 focuses on posttranscriptional events, and Research Project 3 focuses on posttranslational modifications, each contributing to the dysregulated immune response to Ebola virus. The dysregulated immune response is responsible for most of the pathogenesis observed in Ebola virus disease. All projects require the BSL-4 Core (Core B), which will be responsible for performing infections of human immune and nonimmune cells, nonhuman primates, and the initial steps of experiments that involve infectious virus. Importantly, Core B will provide each of the research projects samples from the same experimental samples insuring that data from each project can be compared directly—this is a unique feature of this P01 Program. The Proteogenomics Core (Core C) will be responsible for massive parallel sequencing and mass spectrometry-based studies. The Bioinformatics and Modeling Core (Core D) is critical for generating tools employed in the experimental designs, including statistical help for OMICS experiments, analyzing OMICS data and integrating OMICS data into networks that model the behavior of various cell populations infected with EBOV. The work done in Core D will synthesize a model to explain how transcriptional, posttranscriptional, and posttranslational responses of individual cell populations lead to immune dysregulation. The comprehensive picture painted by this collaborative effort will revolutionize our understanding of the immunopathogenesis of severe acute viral infections (e.g., immune imbalance seen in COVID-19). The Administrative Core (Core A) will be responsible for strategic planning, continual evaluation, and communication and coordination of activities among the various components of the project according to a detailed management plan. The expected outcomes will contribute substantially to our knowledge of the fundamental mechanisms of the immunopathogenesis of EBOV infections toward the development of effective countermeasures. The expected outcomes will include (1) detailed knowledge of transcriptional mechanisms leading to the dysregulated immune response to EBOV, (2) elucidation of the role of posttranscriptional mechanisms in the dysregulated immune response to EBOV, (3) elucidation of the role of posttranslational mechanisms in the dysregulated immune response to EBOV, and (4) experimental validation of the identified pathogenic mechanisms and their targeting. The proposed tightly coordinated and comprehensive analysis has not been done before for any virus.