Assessment of deubiquitinating and deISGylating activity; specificity motifs amon

描述（由申请方提供）：克里米亚-刚果出血热（CCHF）病毒是一种ssRNA（-）内罗病毒，可在人类中引起发热、虚脱和严重腹泻。根据病毒的系统发育变异、传播途径和不同的治疗设施，CCHF的致死率范围为5-70%。最初在俄罗斯和刚果发现的CCHF已迅速蔓延到欧洲、亚洲和非洲的大部分地区。最近，前往受CCHF影响地区的美国公民流量大幅增加，特别是南亚和中亚。因此，存在将CCHF和/或其蜱虫媒介传播到美国的重大风险。目前，没有可用于治疗CCHF的疫苗或预防剂。最近的报道已经鉴定了卵巢肿瘤蛋白酶（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样干扰素刺激基因15（ISG 15）参与干扰素1型免疫应答的下调。此外，vOTU的低序列同源性同源物已被认为在经济破坏性ssRNA（+）动脉炎病毒、猪呼吸和生殖综合征和马动脉炎中发挥类似作用。这一提议将确定去泛素化和去ISGylating活性是否是该蛋白酶亚类的保守功能，并深入了解它们识别Ub和ISG 15的机制。所得到的信息将提供对vOTU在不同病毒中的功能的深入了解，这些功能最终可能在靶向vOTU的药物开发中具有实用性。 公共卫生相关性：克里米亚-刚果出血热和猪呼吸和生殖综合征是危险的新出现的人类和动物疾病，可能造成广泛的健康和经济破坏。这些疾病起源于两个不同的病毒家族，它们被认为具有共同的保守逃避机制，阻碍了人类先天免疫反应。该建议旨在评估该机制，以提供有关开发广泛抗病毒治疗的实用性的信息。

DESCRIPTION (provided by applicant): Crimean-Congo hemorrhagic fever (CCHF) virus is a ssRNA (-) nairovirus that produces fever, prostration, and severe hemorrhages in humans. Fatality rates for CCHF range from 5-70% based on phylogenetic variation of the virus, transmission route, and different treatment facilities. Originally identified in Russia and the Congo, CCHF has rapidly spread across large sections of Europe, Asia, and Africa. Recently, U.S. citizen traffic has increased substantially to the regions affected by CCHF, specifically South Central Asia. As a result, there is a substantial risk for transmission of CCHF and/or its tick vector to the U.S. Currently, there is no vaccine or prophylactic available for treatment of CCHF. Recent reports have identified a viral homologue of the ovarian tumor protease (vOTU) 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-stimulated gene 15 (ISG15). Additionally, a low sequence homology homologue of vOTU has been suggested to perform a similar role in the economically devastating ssRNA (+) arteriviruses, Porcine Respiratory and Reproduction Syndrome and Equine arteritis. This proposal will determine whether deubiquitinating and deISGylating activity is conserved function of this subclass of protease as well as gain insight into their mechanism of recognition for Ub and ISG15. The resulting information will provide insight into the function of vOTUs in different viruses that may ultimately have practicality in the development of prophylactics targeting vOTUs. PUBLIC HEALTH RELEVANCE: Crimean-Congo hemorrhagic Fever and Porcine Respiratory and Reproductive Syndrome are dangerous emerging human and animal diseases that can potentially cause widespread health and economic devastation. These diseases originate from two divergent viral families that have been suggested to share a conserved evasion mechanism that hinders human innate immune response. This proposal serves to evaluate that mechanism in order to provide information on the practicality of developing a broad anti-viral treatment.