Role for polyamines in Ebola Virus Replication

 描述(申请人提供)：丝状病毒科是一个小病毒家族，包括高致病性埃博拉病毒和马尔堡病毒。这些病毒的致死率高达90%。正如最近在西非爆发的埃博拉疫情所强调的那样，丝状病毒具有直接(通过直接致病)和间接(迫使关闭现有诊所和治疗方案，从而引发恐慌)对健康造成不良影响的巨大潜力。尽管已经开发和部署了多种治疗这种疾病的潜在疗法，但目前还不清楚哪些疗法起到了帮助作用。疫情的一个明显教训是，缺乏有关埃博拉等病毒的基本信息，阻碍了有效的控制和治疗。在这种情况下，很明显，埃博拉病毒及其亲属如何利用感染细胞的成分为自己谋利的基本方面仍是未知的。对埃博拉病毒如何“窃取”宿主或识别病毒所需的细胞过程的详细了解，可以提供对病毒一般生物学的重要洞察，并有助于识别可以有效针对阻止病毒复制的宿主过程。这项提议将检验这样一种假设，即多胺及其产物，如非规范氨基酸亚硫氨酸，对于埃博拉病毒的复制是必不可少的。为了验证这一假说，我们将使用针对多胺合成途径的现有小分子，并将使用基因靶向敲除技术来评估多胺合成酶、激动酶和减毒蛋白eIF5A对埃博拉病毒基因表达的重要性。通过这些研究，我们希望确定该途径对病毒基因表达的重要性，并了解多胺途径控制病毒基因表达的机制。确定这一途径对埃博拉病毒复制很重要具有重要的翻译意义，因为已知有许多化合物针对多胺和下丘脑合成途径。其中一些是FDA批准的，一些是高级开发中的。支持我们假设这一途径很重要的数据可能会导致在疾病的动物模型中测试这些化合物。

 DESCRIPTION (provided by applicant): The Filoviridae are a small family of viruses that include the highly pathogenic Ebola and Marburg viruses. These viruses are associated with fatality rates of up to 90%. As has been highlighted during the recent outbreaks of Ebola in Western Africa, filoviruses have tremendous potential for adverse health effects both directly (through direct pathogenesis) and indirectly (forcing the shutdown of existing clinics and treatment programs, sparking panic). Though a variety of potential therapies for the disease have been developed and deployed, it is currently unclear which if any have helped. A clear lesson from the outbreak is that the lack of basic information about viruses like Ebola have hampered effective control and therapy. In this vein, it is clear that basic aspects of how Ebola and its relatives utilize components of infected cells to their advantage are still unknown. A detailed understanding of how Ebola "steals" from its host or identification of cellular processes that the virus requires can offer important insight into both the general biology of the virus and can lead to the identification of host processes that can be effectively targeted to block viral replication. This proposal will test the hypothesis that polyamines and products of polyamines such as the non-canonical amino acid hypusine are essential for Ebola virus replication. To test this hypothesis we will use existing small- molecules that target the polyamine synthesis pathway and we will use gene-targeting knockdown technology to assess the importance of polyamine synthesis enzymes, hypusination enzymes and the hypusinated protein eIF5A on Ebola virus gene expression. Through these studies we hope to determine the importance of this pathway for viral gene expression and understand the mechanism by which the polyamine pathway controls viral gene expression. Identification of this pathway as important for Ebola virus replication has significant translational implications, as there are many compounds that are known to target the polyamine and hypusine synthesis pathways. Some of these are FDA-approved, some are in advanced development. Data supporting our hypothesis that this pathway is important can lead to the testing of these compounds in animal models of disease.