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:10689136
- 负责人:
- 金额:$ 31.89万
- 依托单位:
- 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:
- 关键词:Advanced DevelopmentAfricaAnimal DiseasesAntiviral ResponseAsiaBiochemicalCatalytic DomainCellsCentral AsiaChiropteraComplexCongoCrimean Hemorrhagic FeverCrimean-Congo Hemorrhagic Fever VirusDangerousnessDataDevelopmentDiseaseDistressEconomicsElementsEuropeFDA approvedFamilyFatality rateFeverFoundationsGenesGenomeGlycoproteinsGoalsHealthHemorrhageHomologous GeneHumanImmune EvasionImmune systemImmunityImmunosuppressionIn VitroInnate Immune ResponseInterferonsKnowledgeMeasuresMethodsMolecularMusNairobi Sheep DiseaseNairobi sheep disease virusNairovirusNatural ImmunityPathogenesisPathogenicityPathway interactionsPeptide HydrolasesPhylogenetic AnalysisPlayPost-Translational Protein ProcessingProtease DomainProteinsProteomicsRNA VirusesRNA-Directed RNA PolymeraseRepliconReportingRiskRoleRouteRussiaSeveritiesSheepSourceSpecies SpecificitySpecificityStructureSystemTherapeuticThunderclap HeadachesTimeUbiquitinUbiquitinationUnited StatesVaccinesVariantVertebratesViralViral Hemorrhagic FeversViral ProteinsVirulenceVirulence FactorsVirusVirus InactivationVirus ReplicationX-Ray CrystallographyZoonosesefficacy evaluationemerging human pathogengene producthuman diseasehuman pathogenimmunogenicityimprovedin vitro activityin vivoinnate immune pathwaysinsightmortalityovarian neoplasmparticlepreferencepressureprophylacticprostrationpublic health relevancerecruitresponsereverse geneticstick-borne virustransmission processubiquitin isopeptidasevaccine candidatevector 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)是一种单链RNA(-)奈罗病毒,可引起发热,
虚弱和严重的人类大出血。与CCHFV相关的病死率从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。
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。最近,CCHFV已经显示出它继续传播到
以前天真的地区。与此同时,美国公民的流量大幅增加,达到
CCHFV流行地区,特别是南亚和中亚。因此,存在着巨大的风险
用于将CCHFV和/或其蜱媒传播到美国。有趣的是,CCHFV并不是
只有威胁公众的奈罗病毒。内罗毕羊病病毒(NSDV)以及奈罗病毒
Isyk-kul、Dugbe和Erve可导致不同严重程度的人类疾病和经济困难。那里
目前是否没有疫苗或预防性药物可用于治疗CCHF或任何其他与奈罗病毒相关的疾病?
疾病。有报道称,已发现一种位于卵巢肿瘤蛋白酶(Votu)的病毒同源物
在奈罗病毒基因组中。最近,VOTU通过以下方式逆转翻译后修改的能力
蛋白质泛素(Ub)和Ub样干扰素模拟基因15(ISG15)在一小部分宿主上的表达
通路已被证明在发病机制中起关键作用。此外,CCHFV和其他机构的VOTU
奈洛氏病毒已被发现对ISG15和他们的物种-物种变异敏感
特异性至少包括疾病被最显著地识别的物种。这项提议将
确定vOTUS靶向通路中特定宿主蛋白的特性。这将是
使治疗方法能够保护或提高对这些病毒的特定宿主抑制因子
病毒。该提案还将寻求评估体外活性/底物之间的相关性
这些奈罗病毒VOTU的物种特异性和总体毒力和人畜共患病范围
有问题的奈罗病毒。此外,使用CCHFV候选疫苗的效果与改变
将评估CCHF Votu功能。总之,由此产生的信息将提供关键的洞察力
探讨vOTUS在致病和宿主限制中的作用以及促进其发展
针对VOTU的避孕药。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Scott Dusan Pegan其他文献
Scott Dusan Pegan的其他文献
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{{ truncateString('Scott Dusan Pegan', 18)}}的其他基金
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:
10673300 - 财政年份:2020
- 资助金额:
$ 31.89万 - 项目类别:
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:
10120003 - 财政年份:2020
- 资助金额:
$ 31.89万 - 项目类别:
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:
10774369 - 财政年份:2020
- 资助金额:
$ 31.89万 - 项目类别:
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:
10480951 - 财政年份:2020
- 资助金额:
$ 31.89万 - 项目类别:
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:
10757071 - 财政年份:2020
- 资助金额:
$ 31.89万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 31.89万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 31.89万 - 项目类别:
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:
8827934 - 财政年份:2013
- 资助金额:
$ 31.89万 - 项目类别:
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:
8614887 - 财政年份:2013
- 资助金额:
$ 31.89万 - 项目类别:
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:
9044012 - 财政年份:2013
- 资助金额:
$ 31.89万 - 项目类别:
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