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
基本信息
- 批准号:9217579
- 负责人:
- 金额:$ 24.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-02-05 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAfricaAnimal ModelAntigensAreaArenaviridaeArenavirusAttenuatedAttenuated Live Virus VaccineCaviaCell LineCellsClinicalClinical TrialsCompetenceConsensus SequenceCultured CellsDevelopmentDideoxy Chain Termination DNA SequencingDiseaseEngineeringExhibitsFutureGeneticGenomeGoalsGrowthHeterophile AntigensHumanImmune responseImmunityImmunizeIndividualInfectionInterferonsKnowledgeLabelLassa FeverLassa virusLujo virusLymphocytic choriomeningitis virusMediatingModelingMolecularMorbidity - disease rateMusMutationOld World ArenavirusesPathogenicityPhenotypePopulationProductionPropertyProtocols documentationPublic HealthReassortant VirusesRecombinantsResourcesRibavirinSerial PassageSouth AfricaSymptomsTestingTravelVaccinesViralViral Hemorrhagic FeversVirulenceVirusVirus Diseasesattenuationbasebiodefenseclinically significantcombatdesignepidemiology studygenetic approachin vivointerestmetropolitanmortalitymouse modelneglectnovelnovel strategiespathogenpublic health relevancepyrosequencingresponsereverse genetics
项目摘要
DESCRIPTION (provided by applicant): Several arenaviruses cause hemorrhagic fever (HF) disease in humans and pose a serious public health problem in their endemic regions. Thus, the Old World arenavirus (OWA) Lassa (LASV) infects several hundred thousand individuals yearly in West Africa resulting in a high number of Lassa fever (LF) cases associated with high morbidity and mortality. Moreover, evidence indicates that the worldwide-distributed OWA LCMV is a neglected clinically important human pathogen. In addition, several arenaviruses including LASV and LCMV pose a credible biodefense threat. Existing anti-arenaviral therapy is limited to an off-label use of ribavirin that is only partially effective, and there are no FDA-licensed, or currently in clinical trials, arenavirus vaccines. However, the MOPV/LASV reassortant (ML29) is a candidate live-attenuated vaccine (L-AttV) for LASV that has shown promising results in animal models. Nevertheless, as with many other traditional L-AttV, the mechanism of ML29 attenuation remains unknown, which raises concerns about the phenotypic stability of ML29 in response to additional mutations. The central goal of this application is to test the hypothesis that we can convert a pathogenic OWA into an attenuated form with features of L-AttV via replacement of its L IGR by a genetically defined synthetic S-like IGR (Ssyn). Our hypothesis is supported by our recent following findings: 1) We could rescued rLCMV(IGR/S-S) with the same S-IGR in both S and L genome segments, and found that it was highly attenuated in vivo. 2) Mice immunized with rLCMV(IGR/S-S) were protected against a lethal challenge with wild type (WT) LCMV. 3) We have obtained evidence that a high degree of sequence plasticity within the S IGR is compatible with virus viability, which supports the feasibility of engineering recombinant arenaviruses with a synthetic S IGR (Ssyn) in the L segment as a general molecular strategy for arenavirus attenuation. To test our hypothesis we propose to complete the following specific aims: Aim 1. Characterize rLCMV (IGR/S-Ssyn): We have rescued rLCMV(IGR/S-Ssyn) where a synthetic S IGR (Ssyn) substituted for the L-IGR. We will characterize rLCMV(IGR/S-Ssyn) in cultured cells and using the mouse model of LCMV infection test the hypothesis that rLCMV(IGR/S-Syn) displays key features for L-AttV. Aim 2: Generate and characterize rLASV(IGR/S-Ssyn): We will generate rLASV(IGR/S-Ssyn) and test the hypothesis that it is attenuated in vivo but able to induce protective immunity against a letha challenge with WT LASV in a well-established guinea pig model of LASV infection. Aim 3. Examine the stability of rLCMV(IGR/S-Ssyn): We will test the hypothesis that rLCMV(IGR/S-Ssyn) is genetically stable during multiplication under different growth conditions. The successful completion of this application will uncover a general molecular strategy for arenavirus attenuation that can facilitate a novel strategy to develop L-AttV to combat human pathogenic arenaviruses.
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
- DOI:10.1128/mbio.00186-20
- 发表时间:2020-03-01
- 期刊:
- 影响因子:6.4
- 作者:Cai, Yingyun;Iwasaki, Masaharu;de la Torre, Juan Carlos
- 通讯作者:de la Torre, Juan Carlos
Molecular Engineering of a Mammarenavirus with Unbreachable Attenuation.
具有不可破坏的减毒能力的乳腺病毒的分子工程。
- DOI:10.1128/jvi.01385-22
- 发表时间:2023
- 期刊:
- 影响因子:5.4
- 作者:Sakabe,Saori;Cubitt,Beatrice;Martinez-Sobrido,Luis;delaTorre,JuanC
- 通讯作者:delaTorre,JuanC
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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:
$ 24.06万 - 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:
$ 24.06万 - 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:
10535058 - 财政年份:2022
- 资助金额:
$ 24.06万 - 项目类别:
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:
$ 24.06万 - 项目类别:
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
- 批准号:
9321544 - 财政年份:2017
- 资助金额:
$ 24.06万 - 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:
$ 24.06万 - 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:
$ 24.06万 - 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:
$ 24.06万 - 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:
$ 24.06万 - 项目类别:
Immune cell dynamics during central nervous system viral infection
中枢神经系统病毒感染期间的免疫细胞动力学
- 批准号:
7581118 - 财政年份:2009
- 资助金额:
$ 24.06万 - 项目类别:
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