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: 9171939
• 负责人: Scott Dusan Pegan
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-20 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171939
• 关键词: Affinity; Africa; Animal Diseases; Animals; Antiviral Agents; Antiviral Response; Asia; Biochemical; Bunyaviridae; Central Asia; Cleaved cell; Congo; Crimean Hemorrhagic Fever; Crimean-Congo Hemorrhagic Fever Virus; Dangerousness; Development; Disease; Disease Outcome; Distress; Down-Regulation; Economics; Elements; Engineering; Europe; FDA approved; Family; Far East; Fatality rate; Fever; Genes; Genome; Goals; Hemorrhage; Homologous Gene; Human; Immune System Diseases; Immune response; Immune system; Immunosuppression; In Vitro; Inflammatory; Innate Immune Response; Interferons; Measures; Middle East; Mono-S; Mus; Nairobi Sheep Disease; Nairobi sheep disease virus; Nairovirus; Natural Immunity; Orthobunyavirus; Peptide Hydrolases; Phylogenetic Analysis; Play; Polyubiquitin; Post-Translational Protein Processing; Protease Domain; Proteins; RNA; RNA-Directed RNA Polymerase; Recombinants; Reporting; Risk; Roentgen Rays; Role; Route; Russia; Severities; Specificity; Structure; Substrate Specificity; System; Therapeutic; Thunderclap Headaches; Ticks; Ubiquitin; Ubiquitination; United States; Vaccines; Variant; Viral; Viral Hemorrhagic Fevers; Viral Physiology; Virulence; Virulence Factors; Virus; Virus Inactivation; base; cytokine; experimental study; gene product; health economics; human disease; in vitro activity; in vivo; insight; mortality; ovarian neoplasm; particle; permissiveness; prophylactic; prostration; public health relevance; reverse genetics; transmission process; vector; viral transmission

DESCRIPTION (provided by applicant): 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 he Congo, CCHFV has rapidly spread across large sections of Europe, Asia, and Africa. Recently, 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 Hazara, Dugbe and Erve can cause human disease of varying severity and economic distress. Currently, there is no vaccine or prophylactic available for treatment of CCHF or other any other nairovirus related diseases. Recent reports have identified a viral homologue of the ovarian tumor protease (vOTU) located within the nairovirus genome and implicated its possible involvement in down-regulation of the Interferon type 1 immune response through cleavage of post-translational modifying proteins ubiquitin (Ub) and Ub-like interferon-simulated gene 15 (ISG15). As a result, it has been suggested to be a virulence factor. This proposal will determine whether dual deubiquitinating and deISGylating activities are conserved functions of this subclass of proteases in vitro and in vivo. Additionally, these experiments will gain insight into their mechanism of recognition for Ub and ISG15 allowing greater predictability of currently unknown vOTUs. The proposal will also seek to evaluate a potential correlation between the in vitro activity/substrate specificity of these nairovirus vOTUs and overall virulence of the nairoviruses in question. The resulting information will also provide critical insight into the role of vOTUs ply in viruses that may ultimately have practicality in the development of prophylactics targeting vOTUs.

描述（由申请人提供）：克里米亚-刚果出血热病毒（CCHFV）是一种ssRNA（-）奈罗病毒，可导致人类发热、乏力和严重出血。根据病毒的系统发育变异、传播途径和不同的治疗设施，与CCHFV相关的死亡率在5% - 80%之间。CCHFV最初在俄罗斯和刚果被发现，现已迅速蔓延到欧洲、亚洲和非洲的大部分地区。最近，前往CCHFV流行地区的美国公民交通量大幅增加，特别是中南亚。因此，存在将CCHFV和/或其蜱虫媒介传播到美国的重大风险。有趣的是，CCHFV并不是唯一一种威胁人类健康的病毒