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(申请人提供)：克里米亚-刚果出血热病毒(CCHFV)是一种单链RNA(-)奈罗病毒，可导致人类发烧、虚弱和严重出血。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相关的病死率从5%到80%不等。CCHFV最初发现于俄罗斯和刚果，现已迅速蔓延到欧洲、亚洲和非洲的大片地区。最近，美国公民前往CCHFV流行地区的交通大幅增加，特别是在南亚。因此，CCHFV和/或其蜱媒传播到美国有很大的风险。耐人寻味的是，CCHFV并不是唯一威胁到 公开的。内罗毕羊病病毒(NSDV)以及奈罗病毒哈扎拉、杜格贝和埃尔维可引起不同严重程度的人类疾病和经济困难。目前，没有疫苗或预防药物可用于治疗CCHF或其他任何与奈罗病毒相关的疾病。最近的报道已经发现了位于奈洛病毒基因组中的卵巢肿瘤蛋白酶(Votu)的病毒同源物，并暗示它可能通过切割翻译后修饰蛋白泛素(Ub)和Ub样干扰素模拟基因15(ISG15)而参与下调干扰素1型免疫反应。因此，它被认为是一个毒力因素。这一提议将确定双重去泛素化和去ISGyl化活性是否是这一亚类蛋白酶在体外和体内的保守功能。此外，这些实验将深入了解它们对Ub和ISG15的识别机制，从而能够更好地预测当前未知的vOTU。该提案还将寻求评估这些奈罗病毒vOTU的体外活性/底物特异性与所述奈罗病毒的整体毒力之间的潜在相关性。由此产生的信息还将为VOTU在病毒中的作用提供关键的洞察，这些病毒最终可能在针对VOTU的预防药物的开发中具有实用性。