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: 10689136
• 负责人: Scott Dusan Pegan
• 金额: $ 31.89万
• 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/10689136
• 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-刚果出血热病毒(CCHFV)是一种单链RNA(-)奈罗病毒，可引起发热， 虚弱和严重的人类大出血。与CCHFV相关的病死率从5- 80%基于病毒的系统发育变异、传播途径和不同的治疗设施。 CCHFV最初发现于俄罗斯和刚果，现已迅速蔓延到 欧洲、亚洲和非洲。最近，CCHFV已经显示出它继续传播到 以前天真的地区。与此同时，美国公民的流量大幅增加，达到 CCHFV流行地区，特别是南亚和中亚。因此，存在着巨大的风险 用于将CCHFV和/或其蜱媒传播到美国。有趣的是，CCHFV并不是 只有威胁公众的奈罗病毒。内罗毕羊病病毒(NSDV)以及奈罗病毒 Isyk-kul、Dugbe和Erve可导致不同严重程度的人类疾病和经济困难。那里 目前是否没有疫苗或预防性药物可用于治疗CCHF或任何其他与奈罗病毒相关的疾病？ 疾病。有报道称，已发现一种位于卵巢肿瘤蛋白酶(Votu)的病毒同源物 在奈罗病毒基因组中。最近，VOTU通过以下方式逆转翻译后修改的能力 蛋白质泛素(Ub)和Ub样干扰素模拟基因15(ISG15)在一小部分宿主上的表达 通路已被证明在发病机制中起关键作用。此外，CCHFV和其他机构的VOTU 奈洛氏病毒已被发现对ISG15和他们的物种-物种变异敏感 特异性至少包括疾病被最显著地识别的物种。这项提议将 确定vOTUS靶向通路中特定宿主蛋白的特性。这将是 使治疗方法能够保护或提高对这些病毒的特定宿主抑制因子 病毒。该提案还将寻求评估体外活性/底物之间的相关性 这些奈罗病毒VOTU的物种特异性和总体毒力和人畜共患病范围 有问题的奈罗病毒。此外，使用CCHFV候选疫苗的效果与改变 将评估CCHF Votu功能。总之，由此产生的信息将提供关键的洞察力 探讨vOTUS在致病和宿主限制中的作用以及促进其发展 针对VOTU的避孕药。