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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：
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
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/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

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/文摘