Mechanisms of Ebola virus-mediated inflammatory activation linked to pathogenesis

有史以来最大和最严重的埃博拉病毒（EBOV）疾病（EVD）爆发发生在西非， 2013年至2016年，并导致了令人难以置信的高死亡人数，经济损失和全球焦虑。EVD是一个 是最严重的病毒性疾病之一，其特征在于系统性病毒复制，免疫失调， 凝血病和多器官功能障碍。系统性病毒复制和免疫的协同作用 作为EVD特征的失调导致诱导全身炎症反应综合征 （SIRS），其引起严重的全身病理学。这种复杂的疾病过程很可能使其难以 用仅靶向EBOV生命周期的治疗剂有效治疗严重/致命EVD。因此，我们认为， 了解EBOV诱导SIRS的机制对于开发有效的治疗药物至关重要。 可以抵消异常免疫激活的干预措施。我们已经发现，EBOV VP 40，病毒 基质蛋白，是病毒装配和出芽所必需的，激活宿主炎症反应， 在人体细胞中释放促炎细胞因子。值得注意的是，我们还发现来自 莱斯顿病毒和本迪布焦病毒，它们与EBOV属于同一属，但被认为是 在人类中，与EBOV相比，EBOV是无致病性或致病性较低的，激活炎症途径的效率低于EBOV。 EBOV VP 40，表明VP 40是一种新的毒力决定因子，至少部分负责EBOV的毒力。 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 蛋白质VP 40通过与EBOV相关的新机制激活炎症反应 人类的发病机制。为了理解EBOV发病机制的这一新出现的方面，申请人的研究人员进行了研究。 小组和合作者将追求三个互动的具体目标，如下：（目标1）定义的意义 VP 40介导的炎症激活中的未折叠蛋白反应/ER-核信号通路;（目的2） 确定VP 40与与VP 40介导的 （目的3）确定EBOV VP 40作为炎性活化中的毒力因子的作用; 基因激活和发病机制。该研究为今后的发展提供了重要的基础 暴露后的治疗干预，目标是不受控制的炎症的分子触发， 这些反应是严重EVD晚期的特征。

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.