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

描述（由申请方提供）：克里米亚-刚果出血热病毒（CCHFV）是一种ssRNA（-）内罗病毒，可在人类中引起发热、虚脱和严重腹泻。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。CCHFV最初在俄罗斯和刚果发现，现已迅速蔓延到欧洲、亚洲和非洲的大部分地区。最近，美国公民流量大幅增加，以CCHFV流行的地区，特别是中亚南部。因此，存在将CCHFV和/或其蜱媒传播到美国的重大风险。有趣的是，CCHFV并不是唯一一种威胁人类健康的内罗病毒。 公众内罗毕羊病病毒（NSDV）以及纳罗病毒哈扎拉、杜格贝和欧文可引起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或其他任何其他内罗病毒相关疾病。最近的报道已经鉴定了位于内罗病毒基因组内的卵巢肿瘤蛋白酶（vOTU）的病毒同源物，并暗示其可能通过切割翻译后修饰蛋白泛素（Ub）和Ub样干扰素模拟基因15（ISG 15）参与干扰素1型免疫应答的下调。因此，它被认为是一种毒力因子。这一建议将确定是否双重去泛素化和去ISGylating活动是保守的功能，这一亚类的蛋白酶在体外和体内。此外，这些实验将深入了解它们对Ub和ISG 15的识别机制，从而提高目前未知vOTU的可预测性。该提案还将寻求评估这些内罗病毒vOTU的体外活性/底物特异性与所讨论的内罗病毒的总体毒力之间的潜在相关性。所得到的信息还将提供vOTU层在病毒中的作用的关键见解，其最终可能在靶向vOTU的药物开发中具有实用性。

DESCRIPTION (provided by applicant): 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 he 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 ply in viruses that may ultimately have practicality in the development of prophylactics targeting vOTUs.