Mechanisms of Ebola virus-mediated inflammatory activation linked to pathogenesis

有记录以来规模最大、最严重的埃博拉病毒（EBOV）疾病（EVD）疫情在西非爆发 2013-2016 年，造成了极高的死亡人数、经济损失和全球焦虑。埃博拉病毒病就是其中之一 最严重的病毒性疾病，其特征是系统性病毒复制、免疫失调、 凝血障碍和多器官功能障碍。全身病毒复制和免疫的协同作用 EVD 特征的失调会导致全身炎症反应综合征 (SIRS) 会引起严重的全身病理。这种复杂的疾病过程很可能使其变得困难 使用仅针对埃博拉病毒生命周期的疗法有效治疗严重/致命的埃博拉病毒病。因此， 了解埃博拉病毒引起的 SIRS 机制对于开发有效的治疗方法至关重要 可以抵消异常免疫激活的干预措施。我们发现 EBOV VP40，即病毒 基质蛋白对于病毒组装和出芽至关重要，激活宿主炎症反应并 人体细胞中促炎细胞因子的释放。值得注意的是，我们还发现 VP40 来自 雷斯顿病毒和本迪布焦病毒，与埃博拉病毒属于同一属，但被认为是 在人类中，与 EBOV 相比，非致病性或致病性较低，激活炎症途径的效率低于 EBOV VP40，表明 VP40 是一种新型毒力决定因素，至少部分负责 这些高度相关的病毒的不同发病机制。综上所述，我们假设 EBOV 矩阵 VP40 蛋白通过一种与 EBOV 相关的新机制激活炎症反应 人类的发病机制。为了了解埃博拉病毒发病机制的这一新出现的方面，申请人的 小组和合作者将追求三个互动的具体目标，如下：（目标 1）定义 VP40 介导的炎症激活中未折叠蛋白反应/ER 核信号通路； （目标2） 确定 VP40 与 VP40 介导的宿主转录机制的相互作用 炎症激活； （目标 3）确定 EBOV VP40 作为炎症毒力因子的作用 基因激活和发病机制。拟议的研究将为开发提供重要基础 针对不受控制的炎症的分子触发因素的暴露后治疗干预措施 严重埃博拉病毒病晚期特征的反应。

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.