Mechanisms of Ebola virus-mediated inflammatory activation linked to pathogenesis

埃博拉病毒介导的炎症激活机制与发病机制相关

基本信息

批准号：
10216646
负责人：
Michael A Barry
金额：
$ 69.67万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216646
关键词：
Africa Animal Model Anxiety Blood Coagulation Disorders Bundibugyo virus Case Fatality Rates Cell Nucleus Cell model Cells Cessation of life ChIP-seq Collaborations Containment Critical Pathways Development Disease Disease Outbreaks Disease Progression EP300 gene Ebola Hemorrhagic Fever Ebola virus Economics Epigenetic Process Functional disorder GRP78 gene Gene Activation Gene Expression Genes Genetic Transcription Goals Heat shock proteins Human Immune Immune response Inflammation Mediators Inflammatory Inflammatory Response JUN gene Lead Life Cycle Stages Link MAPK8 gene Mediating Molecular Molecular Target N-terminal Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phosphotransferases Process Protein Family Proteins Proteomics Public Health RNA Polymerase II Recording of previous events Research Research Personnel Research Proposals Reston Reston Ebola virus Role Scheme Signal Pathway Signal Transduction Syndrome Systemic Inflammatory Response Syndrome Testing Therapeutic Intervention Time Tissues Transcription Factor AP-1 Transcriptional Activation Transcriptional Regulation Viral Viral Hemorrhagic Fevers Viral Matrix Proteins Viral Pathogenesis Viral Proteins Virulence Virulence Factors Virus Virus Assembly Virus Diseases Virus Replication Work base chemokine cytokine design effective therapy epigenetic regulation immune activation insight medical countermeasure member next generation novel nuclear factor of activated T-cells, 90 kD particle response reverse genetics sensor therapeutic target therapeutically effective transcription factor transcriptomics vaccine development virus host interaction

项目摘要

The largest and worst Ebola virus (EBOV) disease (EVD) outbreak ever recorded occurred in West Africa from 2013-2016, and resulted in a devastatingly high death toll, economic damages, and global anxiety. EVD is one of the most severe viral diseases, and is characterized by systemic viral replication, immune dysregulation, coagulopathy, and multi-organ dysfunction. The synergistic effects of systemic viral replication and immune dysregulation that characterize EVD lead to the induction of a systemic inflammatory response syndrome (SIRS) that evokes severe systemic pathology. This complicated disease process most likely makes it difficult to effectively treat severe/fatal EVD with therapeutics that target only the EBOV life cycle. Therefore, understanding the mechanisms of EBOV-induced SIRS is crucial for the development of effective therapeutic interventions that can counteract the aberrant immune activation. We have found that EBOV VP40, the viral matrix protein that is essential for virus assembly and budding, activates host inflammatory responses and release of pro-inflammatory cytokines in the human cells. Remarkably, we have also found that VP40 from Reston virus and Bundibugyo virus, which belong to the same genus as EBOV but are thought to be apathogenic or less pathogenic than EBOV in humans, activated the inflammatory pathway less efficiently than EBOV VP40, suggesting that VP40 is a novel virulence determinant at least partially responsible for the differential pathogenesis of these highly related viruses. Taken together, we hypothesize that the EBOV matrix protein VP40 activates an inflammatory response through a novel mechanism, which correlates with EBOV pathogenesis in humans. To understand this newly emerging aspect of EBOV pathogenesis, the applicant's group and collaborators will pursue three interactive specific aims, as follows: (Aim 1) Define the significance of unfolded protein response/ER-nucleus signaling pathway in VP40-mediated inflammatory activation; (Aim 2) Determine the interaction of VP40 with host transcriptional machinery associated with VP40-mediated inflammatory activation; and (Aim 3) Determine the role of EBOV VP40 as a virulence factor in inflammatory gene activation and pathogenesis. The proposed research will provide an essential base for the development of post-exposure therapeutic interventions that target the molecular triggers of the uncontrolled inflammatory responses that characterize the late stages of severe EVD.

有史以来记录的最大和最坏的埃博拉病毒（EBOV）疾病（EVD）发生在西非 2013 - 2016年，导致死亡人数巨大，经济损害和全球焦虑。 EVD是一个最严重的病毒疾病，其特征是全身病毒复制，免疫失调，凝血病和多器官功能障碍。全身病毒复制和免疫的协同作用特征EVD的失调导致诱导全身性炎症综合征（SIRS）唤起严重的全身病理学。这种复杂的疾病过程很可能使其很难用仅针对EBOV生命周期的治疗剂有效地治疗严重/致命的EVD。所以，了解EBOV引起的SIRS的机制对于开发有效的治疗至关重要可以抵消异常免疫激活的干预措施。我们发现病毒EBOV VP40 对于病毒组装和萌芽至关重要的基质蛋白，激活宿主炎症反应和人类细胞中促炎性细胞因子的释放。值得注意的是，我们还发现VP40来自 Reston病毒和Bundibugyo病毒，属于与EBOV相同的属，但被认为是与人类中的EBOV相比，无动于衷或致病性较低，激活炎症途径的效率低于 EBOV VP40，表明VP40是一种新颖的毒力决定因素，至少部分负责这些高度相关病毒的差异发病机理。总之，我们假设EBOV矩阵蛋白质VP40通过一种与EBOV相关的新机制激活炎症反应人类的发病机理。为了了解EBOV发病机理的新出现的方面，申请人的小组和合作者将追求三个交互式特定目的，如下：（目标1）定义的意义 VP40介导的炎症激活中未折叠的蛋白质反应/ER核信号通路；（目标2）确定VP40与与VP40介导的宿主转录机械的相互作用炎症激活；（AIM 3）确定EBOV VP40作为毒力因子在炎症中的作用基因激活和发病机理。拟议的研究将为开发提供基础暴露后治疗干预措施，靶向不受控制的炎症的分子触发因素反应是严重EVD的晚期。