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: 10264937
• 负责人: Scott Dusan Pegan
• 金额: $ 33.1万
• 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/10264937
• 关键词: Advanced Development; Africa; Animal Diseases; Antiviral Agents; 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; Hemorrhage; Homologous Gene; Human; 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; Roentgen Rays; 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; Zoonoses; base; efficacy evaluation; emerging human pathogen; gene product; health economics; 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; vaccine candidate; vector tick; viral transmission

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.

总结/摘要 克里米亚-刚果出血热病毒（CCHFV）是一种引起发热的ssRNA（-）内罗病毒， 人，是一种严重的精神分裂症。与CCHFV相关的死亡率范围为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。 最初在俄罗斯和刚果发现的CCHFV迅速蔓延到大部分地区， 欧洲、亚洲和非洲。最近，CCHFV已经说明了其持续传播到 以前天真的地区。与此同时，美国公民流量大幅增加， CCHFV流行地区，特别是南亚和中亚。因此，存在重大风险 CCHFV和/或其蜱媒传播到美国。有趣的是，CCHFV不是 只有内罗病毒会威胁到公众内罗毕绵羊病病毒（NSDV）以及内罗病毒 伊塞克湖、杜格贝和厄弗可以导致不同严重程度的人类疾病和经济困境。那里 目前没有疫苗或预防剂可用于治疗CCHF或任何其他与内罗病毒相关的疾病 疾病报道已经鉴定了卵巢肿瘤蛋白酶（vOTU）的病毒同源物， 在内罗病毒基因组中。最近，vOTU逆转翻译后修饰的能力被证实是通过逆转翻译后修饰的。 蛋白质泛素（Ub）和Ub样干扰素模拟基因15（ISG 15）在一个狭窄的宿主亚群 已经说明了这些途径对发病机制至关重要。此外，来自CCHFV和其他 已经发现内罗病毒对ISG 15中的种-种变异敏感，并且其 特异性至少包括疾病被最显著地识别的物种。这项建议会 确定vOTU靶向的那些途径内的特定宿主蛋白的身份。这将 使治疗方法，保护，或提高，特定的宿主抑制因子，这些 病毒该提案还将寻求评估体外活性/底物之间的相关性 这些内罗病毒vOTU的种属特异性以及病毒的总体毒力和人畜共患病范围 奈洛病毒此外，使用具有改变的CCHFV疫苗候选物的功效也被证实。 将评估CCHF vOTU功能。综合起来，所产生的信息将提供关键的洞察力 vOTU在致病和宿主限制中的作用，以及促进 针对vOTU的攻击性武器