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：
10774369
负责人：
Scott Dusan Pegan
金额：
$ 7.91万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
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/10774369
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

项目摘要

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 ssRNA (-) 内罗病毒，会引起发烧，与 CCHFV 相关的死亡率为 5-5 倍。 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 最初在俄罗斯和刚果发现，现已迅速传播到该地区的大部分地区。最近，CCHFV 已显示出其持续蔓延到欧洲、亚洲和非洲的能力。与此同时，美国公民的交通量大幅增加。 CCHFV 流行地区，特别是中南亚地区，因此存在很大的风险。有趣的是，CCHFV 并不是传播到美国的病毒。唯一威胁公众的内罗毕羊病病毒（NSDV）以及内罗病毒。伊塞克湖、杜格贝湖和埃尔韦湖可能导致不同严重程度的人类疾病和经济困难。目前尚无疫苗或预防措施可用于治疗 CCHF 或任何其他内罗病毒相关疾病报告已鉴定出卵巢肿瘤蛋白酶 (vOTU) 的病毒同源物。最近，vOTU 能够通过内罗病毒基因组逆转翻译后修饰。一小部分宿主的泛素蛋白 (Ub) 和 Ub 样干扰素模拟基因 15 (ISG15) 此外，CCHFV 和其他途径的 vOTU 也被证明对发病机制至关重要。已发现内罗病毒对 ISG15 及其种属变异敏感特异性至少包括该提案将确定的疾病最显着的物种。确定 vOTU 靶向的那些途径中特定宿主蛋白的身份。启用保护或提高这些疾病的特定宿主抑制因子的治疗方法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 的物种特异性以及该病毒的总体毒力和人畜共患病范围此外，使用 CCHFV 候选疫苗的功效也发生了变化。 CCHF vOTU 功能将被一起评估，由此产生的信息将提供重要的见解。研究 vOTU 在发病机制和宿主限制中的作用并促进发展针对 vOTU 的预防措施。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vaccination with the Crimean-Congo hemorrhagic fever virus viral replicon vaccine induces NP-based T-cell activation and antibodies possessing Fc-mediated effector functions.

DOI：
10.3389/fcimb.2023.1233148
发表时间：
2023
期刊：
Frontiers in cellular and infection microbiology
影响因子：
5.7
作者：
通讯作者：

The interplays between Crimean-Congo hemorrhagic fever virus (CCHFV) M segment-encoded accessory proteins and structural proteins promote virus assembly and infectivity.

DOI：
10.1371/journal.ppat.1008850
发表时间：
2020-09
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Freitas N;Enguehard M;Denolly S;Levy C;Neveu G;Lerolle S;Devignot S;Weber F;Bergeron E;Legros V;Cosset FL
通讯作者：
Cosset FL

Editorial: Ubiquitin and ubiquitin-like modifications in viral infection and innate immunity.

DOI：
10.3389/fimmu.2023.1148296
发表时间：
2023
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

The Structure and Immune Regulatory Implications of the Ubiquitin-Like Tandem Domain Within an Avian 2'-5' Oligoadenylate Synthetase-Like Protein.

DOI：
10.3389/fimmu.2021.794664
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Shepard JD;Freitas BT;Rodriguez SE;Scholte FEM;Baker K;Hutchison MR;Longo JE;Miller HC;O'Boyle BM;Tandon A;Zhao P;Grimsey NJ;Wells L;Bergeron É;Pegan SD
通讯作者：
Pegan SD

Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus.

DOI：
10.1038/s41467-022-34923-0
发表时间：
2022-11-26
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Durie, Ian A.;Tehrani, Zahra R.;Karaaslan, Elif;Sorvillo, Teresa E.;McGuire, Jack;Golden, Joseph W.;Welch, Stephen R.;Kainulainen, Markus H.;Harmon, Jessica R.;Mousa, Jarrod J.;Gonzalez, David;Enos, Suzanne;Koksal, Iftihar;Yilmaz, Gurdal;Karakoc, Hanife Nur;Hamidi, Sanaz;Albay, Cansu;Spengler, Jessica R.;Spiropoulou, Christina F.;Garrison, Aura R.;Sajadi, Mohammad M.;Bergeron, Eric;Pegan, Scott D.
通讯作者：
Pegan, Scott D.