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

总结/摘要 克里米亚-刚果出血热病毒（CCHFV）是一种引起发热的ssRNA（-）内罗病毒， 人，是一种严重的精神分裂症。与CCHFV相关的死亡率范围为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。 最初在俄罗斯和刚果发现的CCHFV迅速蔓延到大部分地区， 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流行，特别是中亚南部。因此，存在重大风险， CCHFV和/或其蜱媒传播到美国。有趣的是，CCHFV不是唯一的 威胁公众的内罗病毒内罗毕绵羊病病毒（NSDV）以及内罗病毒 哈扎拉人、杜格贝人和欧文人会导致不同严重程度的人类疾病和经济困境。 目前，没有疫苗或预防剂可用于治疗CCHF或其他任何其他疾病。 内罗病毒相关疾病。最近的报道已经确定了一种卵巢肿瘤的病毒同源物 蛋白酶（vOTU）位于内罗病毒基因组内，并暗示其可能参与 干扰素1型免疫应答通过翻译后切割下调 修饰蛋白泛素（Ub）和Ub样干扰素模拟基因15（ISG 15）。因此， 被认为是一种毒力因子。这项提议将决定是否双去泛素化 和去ISGylating活性是该蛋白酶亚类在体外和体内的保守功能。 此外，这些实验将深入了解它们对Ub和ISG 15的识别机制 从而允许对当前未知的vOTU的更大的可预测性。该提案还将寻求评估一项 这些内罗病毒vOTU的体外活性/底物特异性之间的潜在相关性， 所述内罗病毒的总体毒力。由此产生的信息还将提供关键的 深入了解vOTU在病毒中的作用，最终可能在开发中具有实用性 针对vOTU的攻击性武器

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.