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)疫情发生在西非 2013-2016年，并导致了毁灭性的高死亡人数、经济损失和全球焦虑。EVD是其中之一 是最严重的病毒性疾病之一，其特点是系统性病毒复制，免疫失调， 凝血障碍和多器官功能障碍。系统性病毒复制与免疫的协同效应 以EVD为特征的调节失调导致全身炎症反应综合征的诱导 (SIRS)这会引起严重的全身病理。这种复杂的疾病过程很可能使它变得困难 使用仅针对EBOV生命周期的疗法有效治疗严重/致命的埃博拉病毒。因此， 了解EBOV诱导SIRS的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病毒 对病毒组装和萌发至关重要的基质蛋白，激活宿主炎症反应和 在人类细胞中释放促炎细胞因子。值得注意的是，我们还发现VP40来自 莱斯顿病毒和本迪布乔病毒，与EBOV属于同一属，但被认为是 在人类中无致病性或致病性低于EBOV，激活炎症途径的效率低于EBOV EBOV VP40，提示VP40是一种新的毒力决定簇，至少部分地与EBOV VP40有关 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EBOV发病机制的这一新方面，申请者的 小组和合作者将追求三个互动的具体目标，如下：(目标1)确定 VP40介导的炎症激活中未折叠蛋白反应/内质网-核信号通路；(目标2) 确定VP40与宿主转录机制的相互作用 炎症激活；以及(目的3)确定EBOV VP40作为毒力因子在炎症中的作用 基因激活与发病机制。拟议的研究将为发展提供必要的基础。 针对失控炎症的分子触发因素的暴露后治疗干预 严重埃博拉病晚期的反应。

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.