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

描述（由申请人提供）：克里米亚-刚果出血热病毒（CCHFV）是一种ssRNA（-）奈罗病毒，可导致人类发热、乏力和严重出血。根据病毒的系统发育变异、传播途径和不同的治疗设施，与CCHFV相关的死亡率在5% - 80%之间。CCHFV最初在俄罗斯和刚果被发现，现已迅速蔓延到欧洲、亚洲和非洲的大部分地区。最近，前往CCHFV流行地区的美国公民交通量大幅增加，特别是中南亚。因此，存在将CCHFV和/或其蜱虫媒介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病毒

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.