Origin of the innate immunity suppression caused by nairovirus' protease activity

摘要/摘要 克里米亚-刚果出血热病毒(CCHFV)是一种单链RNA(-)奈罗病毒，可引起发热， 虚弱和严重的人类大出血。与CCHFV相关的病死率从5- 80%基于病毒的系统发育变异、传播途径和不同的治疗设施。 CCHFV最初发现于俄罗斯和刚果，现已迅速蔓延到 欧洲、亚洲和非洲。最近，前往这些地区的美国公民流量大幅增加 CCHFV的地方性流行，特别是南亚。因此，有很大的风险 将猪瘟病毒和/或其蜱媒传播到美国。有趣的是，CCHFV并不是唯一 威胁公众的奈罗病毒。内罗毕羊病病毒(NSDV)以及奈罗病毒 哈扎拉、杜格贝和埃尔维可导致不同严重程度的人类疾病和经济困难。 目前，没有疫苗或预防药物可用于治疗CCHF或其他任何其他疾病 奈罗病毒相关疾病。最近的报道发现了一种卵巢肿瘤的病毒同源物。 位于奈洛病毒基因组中的蛋白水解酶(Votu)，可能参与了 翻译后切割下调干扰素1型免疫应答 修饰蛋白泛素(Ub)和类Ub干扰素模拟基因15(ISG15)。因此，它已经 被认为是一个致病因素。这一提议将决定双重去泛素 去ISGylating活性是这一亚类酶在体外和体内的保守功能。 此外，这些实验还将深入了解它们对Ub和ISG15的识别机制 从而允许对当前未知的VOTU进行更大的可预测性。该提案还将寻求评估一项 这些奈洛病毒vOTU的体外活性/底物特异性与 有问题的奈罗病毒的整体毒力。由此产生的信息还将提供关键的 洞察vOTU在病毒中扮演的角色，这些病毒最终可能在开发中具有实用性 针对VOTU的避孕药。

Summary/Abstract Crimean-Congo hemorrhagic fever virus (CCHFV) is a ssRNA (-) nairovirus that produces fever, prostration, and severe hemorrhages in humans. Fatality rates associated with CCHFV range from 5- 80% based on phylogenetic variation of the virus, transmission route, and different treatment facilities. Originally identified in Russia and the Congo, CCHFV has rapidly spread across large sections of Europe, Asia, and Africa. Recently, U.S. citizen traffic has increased substantially to the regions endemic with CCHFV, specifically South Central Asia. As a result, there is a substantial risk for transmission of CCHFV and/or its tick vector to the United States. Intriguingly, CCHFV is not the only nairovirus that threatens the public. Nairobi Sheep Disease virus (NSDV) as well as nairoviruses Hazara, Dugbe and Erve can cause human disease of varying severity and economic distress. Currently, there is no vaccine or prophylactic available for treatment of CCHF or other any other nairovirus related diseases. Recent reports have identified a viral homologue of the ovarian tumor protease (vOTU) located within the nairovirus genome and implicated its possible involvement in down-regulation of the Interferon type 1 immune response through cleavage of post-translational modifying proteins ubiquitin (Ub) and Ub-like interferon-simulated gene 15 (ISG15). As a result, it has been suggested to be a virulence factor. This proposal will determine whether dual deubiquitinating and deISGylating activities are conserved functions of this subclass of proteases in vitro and in vivo. Additionally, these experiments will gain insight into their mechanism of recognition for Ub and ISG15 allowing greater predictability of currently unknown vOTUs. The proposal will also seek to evaluate a potential correlation between the in vitro activity/substrate specificity of these nairovirus vOTUs and overall virulence of the nairoviruses in question. The resulting information will also provide critical insight into the role of vOTUs play in viruses that may ultimately have practicality in the development of prophylactics targeting vOTUs.