Modulation of Lassa Virus vRNP Activity By Host Cell Factors
宿主细胞因子对拉沙病毒 vRNP 活性的调节
基本信息
- 批准号:9321544
- 负责人:
- 金额:$ 31.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-15 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:AfricaAntiviral AgentsAntiviral TherapyApplications GrantsAreaArenaviridaeArenavirusBiologicalBiological AssayCRISPR/Cas technologyCell DensityCell LineCell SurvivalCellsCellular Metabolic ProcessCellular biologyCollaborationsComplexContainmentDrug resistanceEpithelialFatality rateFoundationsGene ExpressionGenerationsGenesGeneticGenetic TranscriptionGenomic LibraryHealthHepatocyteHumanHuman GenomeIndividualKnowledgeLabelLassa FeverLassa virusLuciferasesLymphocytic choriomeningitis virusMeasuresMediatingMolecular BiologyMonitorMorbidity - disease rateNucleoproteinsOld World ArenavirusesPathogenesisPathogenicityPharmacologyPhenotypePolymeraseProcessProteinsRNARNA InterferenceRNA VirusesRNA interference screenRNA replicationReadinessReadingRecording of previous eventsReporterReporter GenesRibavirinRibonucleoproteinsSmall Interfering RNASpecificityTechnologyTherapeuticToxic effectTranscription ProcessTransfectionTravelVaccinesValidationVariantViral GenomeViral Hemorrhagic FeversVirusVirus Replicationbasebiodefensecell typeclinically significantcombatdesignfunctional genomicsgenome-wide analysisinsightknock-downloss of functionmonocytemortalityneglectnovelnovel strategiespathogenstemtransmission processviral RNA
项目摘要
Project Summary:
The arenavirus Lassa (LASV) infects several hundred thousand individuals yearly in West Africa resulting in a
high number of Lassa fever (LF) cases that are associated with high morbidity and mortality. In addition, LASV
is a credible biodefense threat. There are not FDA-licensed vaccines and current anti-arenaviral therapy is
limited to the off-label use of ribavirin that is only partially effective. The significance of LASV in human health
and biodefense readiness, together with the limited existing armamentarium to combat them, underscore the
unmet need for novel anti-LASV therapeutics. We hypothesize that selective targeting of host cell factors
required for virus RNA replication and gene transcription, processes mediated by the virus ribonucleoprotein
(vRNP), but dispensable for normal host cell metabolism and survival, represents a novel strategy to combat
human pathogenic arenaviruses. This approach would minimize the common problem in antiviral therapy
posed by the emergence of drug resistant variants. To implement this strategy, we propose to conduct a siRNA
genome-wide screen to identify host cell genes required for the activity of LASV vRNP. For this we have
generated a virus-free cell line containing a functional LASV vRNP (LASV/vRNP) that directs expression of the
ZsGreen and Gaussia luciferase (Gluc) reporter genes (RG) from a virus-like RNA, aka minigenome (MG), and
shown that RG expression (RGE) accurately reflect vRNP activity. Our specific aims (SA) are:
SA 1. Conduct siRNA-based genome-wide screen to identify host cell factors that contribute to the activity of
LASV vRNP. We have used our LASV/vRNP cells to establish conditions compatible with genetic HTS to
identify modifiers of LASV vRNP activity. We propose to screen our LASV/vRNP cells against Dharmacon’s
On-Target-Plus human genome library to identify host cell genes that inhibit LASV vRNP activity as reflected
by reduction of Gluc and ZsGreen readings.
SA 2. Hit validation. We will determine levels of LASV MG-directed expression levels of a different reporter
gene, CAT, in cells where hit candidates have been subjected to RNAi-mediated knock down, complete loss-
of-function via CRISPR-Cas9, and pharmacological interference. To assess hit specificity we will perform MG
assays with other RNA viruses. Further hit validation will be done using cell types that are biologically relevant
in the context of LASV including human epithelial and endothelia cells, hepatocytes and monocytes.
Knowledge derived from these studies will provide: 1) the foundation for designing antiviral strategies aimed at
targeting host cell factors required for essential viral RNA biosynthetic processes, and 2) novel insights about
arenavirus-host interactions that will contribute to a better understanding of arenavirus pathogenesis.
项目总结:
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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Juan C. de la Torre其他文献
Reverse-genetic approaches to the study of Borna disease virus
伯尔尼病病毒研究的反向遗传学方法
- DOI:
10.1038/nrmicro1489 - 发表时间:
2006-09-11 - 期刊:
- 影响因子:103.300
- 作者:
Juan C. de la Torre - 通讯作者:
Juan C. de la Torre
Establishment of recombinant ML29 platform for the generation of polyvalent live-attenuated vaccines against Lassa virus and other infectious agents
建立重组 ML29 平台,用于生产针对拉沙病毒和其他传染原的多价减毒活疫苗
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Masaharu Iwasaki;Beatrice Cubitt;Daisuke Motooka;Dylan M. Johnson;Igor S. Lukashevich;Juan C. de la Torre - 通讯作者:
Juan C. de la Torre
Juan C. de la Torre的其他文献
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{{ truncateString('Juan C. de la Torre', 18)}}的其他基金
Improving The Scripps Research Institute BSL3 Capabilities to Combat Viruses of Pandemic Concern
提高斯克里普斯研究所 BSL3 对抗流行病病毒的能力
- 批准号:
10611798 - 财政年份:2022
- 资助金额:
$ 31.25万 - 项目类别:
Designing mammarenavirus live vaccines with unbreachable attenuation
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- 批准号:
10535058 - 财政年份:2022
- 资助金额:
$ 31.25万 - 项目类别:
Designing mammarenavirus live vaccines with unbreachable attenuation
设计具有不可破坏的减毒效果的乳腺病毒活疫苗
- 批准号:
10664016 - 财政年份:2022
- 资助金额:
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Development and validation of antivirals against hemorrhagic fever viruses of pandemic concern
针对大流行病的出血热病毒的抗病毒药物的开发和验证
- 批准号:
10514329 - 财政年份:2022
- 资助金额:
$ 31.25万 - 项目类别:
A General Molecular Strategy for Attenuation of Human Pathogenic Arenaviruses
人类致病性沙粒病毒减毒的通用分子策略
- 批准号:
9217579 - 财政年份:2016
- 资助金额:
$ 31.25万 - 项目类别:
A General Molecular Strategy for Attenuation of Human Pathogenic Arenaviruses
人类致病性沙粒病毒减毒的通用分子策略
- 批准号:
9112491 - 财政年份:2016
- 资助金额:
$ 31.25万 - 项目类别:
Activity-Based Protein Profiling of Arenavirus-Host Interactions
基于活性的沙粒病毒-宿主相互作用的蛋白质分析
- 批准号:
8970028 - 财政年份:2015
- 资助金额:
$ 31.25万 - 项目类别:
Profiling Serine Hydrolase Activity At The Virus-Host Interface
病毒-宿主界面丝氨酸水解酶活性分析
- 批准号:
8869489 - 财政年份:2015
- 资助金额:
$ 31.25万 - 项目类别:
Profiling Serine Hydrolase Activity At The Virus-Host Interface
病毒-宿主界面丝氨酸水解酶活性分析
- 批准号:
9085225 - 财政年份:2015
- 资助金额:
$ 31.25万 - 项目类别:
Immune cell dynamics during central nervous system viral infection
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- 批准号:
7581118 - 财政年份:2009
- 资助金额:
$ 31.25万 - 项目类别:
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