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

内罗病毒蛋白酶活性引起先天免疫抑制的起源

• 批准号: 9044012
• 负责人: Scott Dusan Pegan
• 金额: $ 1.66万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-20 至 2015-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044012
• 关键词: Affinity; Africa; Animal Diseases; Animals; Antiviral Agents; Antiviral Response; Asia; Binding; Biochemical; Bunyaviridae; Central Asia; Cleaved cell; Congo; Crimean Hemorrhagic Fever; Crimean-Congo Hemorrhagic Fever Virus; Development; Disease; Disease Outcome; Distress; Down-Regulation; Economics; Elements; Endogenous Retroviruses; Engineering; Europe; FDA approved; Family; Far East; Fever; Genes; Genome; Goals; Health; Hemorrhage; Homologous Gene; Human; Human Ubiquitin; Immune response; Immune system; In Vitro; Inflammatory; Interferon Suppression; Interferons; Measures; Middle East; Mono-S; Mus; Nairobi Sheep Disease; Nairobi sheep disease virus; Nairovirus; Natural Immunity; Peptide Hydrolases; Phylogenetic Analysis; Play; Polyubiquitin; Post-Translational Protein Processing; Protease Domain; Proteins; RNA; RNA-Directed RNA Polymerase; Recombinants; Relative (related person); Reporting; Risk; Roentgen Rays; Role; Route; Russia; Severities; Specificity; Structure; Substrate Specificity; System; Therapeutic; Thunderclap Headaches; Ticks; Ubiquitin; Ubiquitination; United States; Vaccines; Variant; Viral; Viral Hemorrhagic Fevers; Virulence; Virulence Factors; Virus; base; cytokine; health economics; human disease; in vitro activity; in vivo; insight; mortality; ovarian neoplasm; particle; prophylactic; prostration; research study; reverse genetics; trafficking; transmission process; vector

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.

描述（由申请人提供）：Crimean-Congo出血热病毒（CCHFV）是一种ssRNA（ - ）奈罗内病毒，可在人类中产生发烧，俯卧和严重的出血。与CCHFV相关的死亡率范围为5-80％，基于病毒，传播途径和不同治疗设施的系统发育变化。 CCHFV最初在俄罗斯和他的刚果中被确定，已迅速分布在欧洲，亚洲和非洲的大部分地区。最近，美国公民的交通已大大增加了与CCHFV，特别是中亚南亚地区流行的地区。结果，将CCHFV和/或其tick矢量传输到美国存在很大的风险。有趣的是，CCHFV并不是唯一威胁威胁 民众。内罗毕绵羊疾病病毒（NSDV）以及奈罗维病毒Hazara，Dugbe和Erve可能导致严重性和经济困扰的人类疾病。当前，尚无可用于治疗CCHF或其他任何奈罗内罗病毒相关疾病的疫苗或预防性。最近的报道已经确定了位于奈罗维病毒基因组中的卵巢肿瘤蛋白酶（fotu）的病毒同源物，并暗示了其可能参与下调1型​​干扰素1型免疫反应，通过切割后翻译后修饰后修饰蛋白（UB）泛素（UB）泛素（UB）和UB型干扰素含量的基因15（ISG15）（ISG15（ISG15））。结果，已建议它是毒力因素。该提案将确定双泛素化和去摩式活性是否是该蛋白酶在体外和体内的保守功能。此外，这些实验将深入了解其对UB和ISG15的识别机制，从而使目前未知的投票能力更大。该提案还将寻求评估这些奈罗内病毒投票的体外活性/底物特异性与所讨论的奈罗内病毒的整体毒力之间的潜在相关性。最终的信息还将为投票中的作用提供重要的见解，这些病毒在针对投票的预防性发展方面可能最终具有实用性的病毒中。