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: 8827934
• 负责人: Scott Dusan Pegan
• 金额: $ 25.11万
• 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 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827934
• 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; 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; Simulate; 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; positional cloning; prophylactic; prostration; public health relevance; research study; trafficking; transmission process; vector

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.

摘要/摘要 克里米亚 - 隆戈出血性发烧病毒（CCHFV）是一种ssRNA（ - ）奈罗内那病毒，发烧， 人类的俯卧和严重的出血。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最初在俄罗斯和刚果中确定，已迅速扩展到大部分地区 欧洲，亚洲和非洲。最近，美国公民的交通大大增加了该地区 CCHFV的地方性，特别是中亚中亚。结果，有很大的风险 将CCHFV和/或其壁虱向量传输到美国。有趣的是，CCHFV不是唯一的 威胁公众的奈罗内病毒。内罗毕绵羊病毒（NSDV）以及奈罗维病毒 Hazara，Dugbe和Erve可能会导致人类疾病的严重程度和经济困扰。 目前，尚无疫苗或预防性可用于治疗CCHF或其他任何其他疫苗 奈罗内病毒相关疾病。最近的报告已经确定了卵巢肿瘤的病毒同源物 位于奈罗内病毒基因组内的蛋白酶（votu），并暗示了其可能参与 干扰素1型免疫反应的下调通过翻译后的裂解 修饰蛋白质泛素（UB）和UB样干扰素模拟的基因15（ISG15）。结果，它具有 被认为是毒力因子。该建议将确定双泛素化是否 除去的活动是体外和体内蛋白酶亚类的保守功能。 此外，这些实验将深入了解其对UB和ISG15的识别机制 允许目前未知的投票更大的可预测性。该提案还将寻求评估 这些奈罗内病毒投票的体外活性/底物特异性之间的潜在相关性 奈罗内病毒的总体毒力。最终的信息还将提供关键 洞悉选票在病毒中的作用，这些病毒最终可能在发展中具有实用性 针对投票的预言。