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

基本信息

批准号：
9171939
负责人：
Scott Dusan Pegan
金额：
$ 30.88万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
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/9171939
关键词：
Affinity Africa Animal Diseases Animals Antiviral Agents Antiviral Response Asia Biochemical Bunyaviridae Central Asia Cleaved cell Congo Crimean Hemorrhagic Fever Crimean-Congo Hemorrhagic Fever Virus Dangerousness Development Disease Disease Outcome Distress Down-Regulation Economics Elements Engineering Europe FDA approved Family Far East Fatality rate Fever Genes Genome Goals Hemorrhage Homologous Gene Human Immune System Diseases Immune response Immune system Immunosuppression In Vitro Inflammatory Innate Immune Response Interferons Measures Middle East Mono-S Mus Nairobi Sheep Disease Nairobi sheep disease virus Nairovirus Natural Immunity Orthobunyavirus Peptide Hydrolases Phylogenetic Analysis Play Polyubiquitin Post-Translational Protein Processing Protease Domain Proteins RNA RNA-Directed RNA Polymerase Recombinants 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 Viral Physiology Virulence Virulence Factors Virus Virus Inactivation base cytokine experimental study gene product health economics human disease in vitro activity in vivo insight mortality ovarian neoplasm particle permissiveness prophylactic prostration public health relevance reverse genetics transmission process vector viral transmission

项目摘要

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）：克里米亚-刚果出血热病毒（CCHFV）是一种 ssRNA (-) 内罗病毒，可导致人类发烧、虚脱和严重出血。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 相关的死亡率范围为 5-80%。 CCHFV 最初在俄罗斯和刚果发现，现已迅速传播到欧洲、亚洲和非洲的大部分地区。最近，前往 CCHFV 流行地区（特别是南中亚）的美国公民流量大幅增加。因此，CCHFV 和/或其蜱虫媒介传播到美国的风险很大。有趣的是，CCHFV 并不是唯一威胁人类健康的内罗病毒。民众。内罗毕羊病病毒 (NSDV) 以及内罗毕病毒哈扎拉病毒、杜格贝病毒和埃尔韦病毒可导致不同严重程度的人类疾病和经济困难。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。最近的报告发现，内罗病毒基因组内存在卵巢肿瘤蛋白酶 (vOTU) 的病毒同源物，并暗示其可能通过裂解翻译后修饰蛋白泛素 (Ub) 和 Ub 参与下调干扰素 1 型免疫反应。类干扰素模拟基因 15 (ISG15)。因此，它被认为是一种毒力因子。该提案将确定双重去泛素化和去糖基化活性是否是该蛋白酶亚类在体外和体内的保守功能。此外，这些实验将深入了解它们对 Ub 和 ISG15 的识别机制，从而对当前未知的 vOTU 具有更大的可预测性。该提案还将寻求评估这些内罗病毒 vOTU 的体外活性/底物特异性与相关内罗病毒的整体毒力之间的潜在相关性。由此产生的信息还将为 vOTU 在病毒中的作用提供重要的见解，最终可能在针对 vOTU 的预防剂的开发中具有实用性。