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: 10757071
• 负责人: Scott Dusan Pegan
• 金额: $ 7.92万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757071
• 关键词: Advanced Development; Africa; Animal Diseases; Antiviral Response; Asia; Biochemical; Catalytic Domain; Cells; Central Asia; Chiroptera; Complex; Congo; Crimean Hemorrhagic Fever; Crimean-Congo Hemorrhagic Fever Virus; Dangerousness; Data; Development; Disease; Distress; Economics; Elements; Europe; FDA approved; Family; Fatality rate; Fever; Foundations; Genes; Genome; Glycoproteins; Goals; Health; Hemorrhage; Homologous Gene; Human; Immune Evasion; Immune system; Immunity; Immunosuppression; In Vitro; Innate Immune Response; Interferons; Knowledge; Measures; Methods; Molecular; Mus; Nairobi Sheep Disease; Nairobi sheep disease virus; Nairovirus; Natural Immunity; Pathogenesis; Pathogenicity; Pathway interactions; Peptide Hydrolases; Phylogenetic Analysis; Play; Post-Translational Protein Processing; Protease Domain; Proteins; Proteomics; RNA Viruses; RNA-Directed RNA Polymerase; Replicon; Reporting; Risk; Role; Route; Russia; Severities; Sheep; Source; Species Specificity; Specificity; Structure; System; Therapeutic; Thunderclap Headaches; Time; Ubiquitin; Ubiquitination; United States; Vaccines; Variant; Vertebrates; Viral; Viral Hemorrhagic Fevers; Viral Proteins; Virulence; Virulence Factors; Virus; Virus Inactivation; Virus Replication; X-Ray Crystallography; Zoonoses; efficacy evaluation; emerging human pathogen; gene product; human disease; human pathogen; immunogenicity; improved; in vitro activity; in vivo; innate immune pathways; insight; mortality; ovarian neoplasm; particle; preference; pressure; prophylactic; prostration; public health relevance; recruit; response; reverse genetics; tick-borne virus; transmission process; ubiquitin isopeptidase; vaccine candidate; vector tick

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, CCHFV has illustrated its continued ability to spread into previously naive regions. At the same time, 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 Issyk-kul, Dugbe and Erve can cause human disease of varying severity and economic distress. There is no vaccine or prophylactic currently available for treatment of CCHF or any other nairovirus related disease. Reports have identified a viral homologue of the ovarian tumor protease (vOTU) located within the nairovirus genome. Recently, vOTUs’ ability to reverse post-translational modification by proteins ubiquitin (Ub) and Ub-like interferon-simulated gene 15 (ISG15) on a narrow subset of host pathways has been illustrated to be critical to pathogenesis. Also, vOTUs from CCHFV and other nairoviruses have been found to be sensitive to species-species variations in ISG15 and their specificity includes at least the species that disease is most prominently identified. This proposal will determine the identity of specific host proteins within those pathways targeted by vOTUs. This will enable therapeutic approaches that protect, or elevate, specific host inhibitory factors for these viruses. The proposal will also seek to evaluate the correlation between the in vitro activity/substrate species-specificity of these nairovirus vOTUs and overall virulence and zoonotic range of the nairoviruses in question. Additionally, the efficacy of using CCHFV vaccine candidates with altered CCHF vOTU functions will be assessed. Together, the resulting information will provide critical insight into the role of vOTUs play in pathogenesis and host restriction as well as advance 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， 人类的程序和严重的出血。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，CCHFV说明了其持续扩散的能力 以前天真的区域。同时，美国公民的交通大大增加了 带有CCHFV的区域，特别是亚洲中南部。结果，存在很大的风险 用于将CCHFV和/或其tick矢量传输到美国。有趣的是，CCHFV不是 只有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 Issyk-Kul，Dugbe和Erve可能会引起人类疾病的严重程度和经济困扰。那里 目前尚无疫苗或预防性可用于治疗CCHF或任何其他与奈罗内病毒有关的治疗 疾病。报告已经确定了位于卵巢肿瘤蛋白酶（fotu）的病毒同源物 在奈罗内病毒基因组中。最近，投票能够通过 蛋白质泛素（UB）和UB样干扰素模拟的基因15（ISG15）在狭窄的宿主子集上 途径已被说明对发病机理至关重要。另外，来自CCHFV和其他的投票 已经发现奈罗病毒对ISG15及其物种种类的变化很敏感 特异性至少包括最明显地鉴定出疾病的物种。该提议将 确定在投票目标中的那些途径中特定宿主蛋白的身份。这会 启用保护或提升特定宿主抑制因素的治疗方法 病毒。该提案还将寻求评估体外活性/底物之间的相关性 这些奈罗内病毒投票以及整体病毒和人畜共患病的物种特异性 奈罗内病毒。此外，使用CCHFV疫苗随着改变的效率 CCHF投票功能将进行评估。由此产生的信息将提供关键的见解 进入选票在发病机理和宿主限制中的作用，并提高发展 针对投票的预言。