Characterization of a human-specific positive regulator of flavivirus infection
黄病毒感染的人类特异性正调节因子的表征
基本信息
- 批准号:10381448
- 负责人:
- 金额:$ 10.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-12 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAngolaAreaAttenuatedAwardBindingBinding SitesBloodBrazilCareer Transition AwardCell Culture SystemCellsClinical ManagementCollaborationsComplexCulicidaeDataDengue InfectionDengue VirusDependenceDevelopmentDiseaseDisease OutbreaksDoseElementsEventFlavivirusFlavivirus InfectionsFundingFutureGenomeGoalsHematopoieticHepatocyteHumanHuman Cell LineImmune systemIn VitroInbreedingInfectionInfectious AgentIntegration Host FactorsKnowledgeLife Cycle StagesLightMass VaccinationsMedicalMicroRNAsMolecularMolecular VirologyMusMutationNucleotidesOligonucleotidesPathogenicityPersonsPhenotypePhysiologicalPolyproteinsPopulationPositioning AttributePostdoctoral FellowPrimatesProteinsRNARNA VirusesRNA replicationRegulationResearchRiskRoleTechnologyTestingTherapeuticTimeTimeLineTissuesTrainingTranslationsTropismUnited States National Institutes of HealthVaccinationVaccinesViralViral GenomeVirulentVirusVirus ReplicationWorkYellow FeverYellow Fever VaccineYellow Fever Virus InfectionYellow fever virusZika Viruscareercell typedetection methodeffective therapyexperimental studygenome-widehealth economicshumanized mousein vivoin vivo Modelinhibitorinterestloss of functionmembermouse modelmutantnovelnovel strategiesnovel therapeutic interventionoverexpressionparticlepathogenpathogenic virusprofessorprogramstherapeutically effectivetooltranscriptomicsunvaccinatedviral RNAvirus host interaction
项目摘要
Project Summary/Abstract
Flaviviruses such as yellow fever virus (YFV), Zika virus (ZIKV) or Dengue virus (DENV) are cause of great
health and economic concerns worldwide. YFV is the prototypical member of the flavivirus genus, and one of
the first human pathogenic viruses that has been identified. Despite the development of a very potent vaccine in
the 1930’s, YFV still represents a real theat. Recent outbreaks in Angola and Brazil, over the past two years,
occurred in areas with low vaccination coverage. These resurgence events have exemplified the threat and have
highlighted the need for the protection of an estimated 400 to 500 million people worldwide. Facing a significant
vaccine shortage, fractional doses of vaccine are now used during vaccination campaigns despite no/limited
evidence of long-term protection, hence underscoring the urgent necessity of developing novel strategies to
clinically manage future YFV outbreaks. Our knowledge of the YFV infectious cycle in vitro and in vivo is
extremely limited which has ultimately hampered the development of specific therapies to treat YFV infection, as
none is currently available. I recently identified a novel host regulator of YFV infection in human cells that is
required for effective YFV infection and replication in vitro. As it is not expressed in mice, this factor could also
contribute to the human/primate-specific tropism of YFV. Building on a robust set of preliminary data, I
hypothesize that this factor regulates RNA replication or protein translation through direct binding to viral
elements. In Aim 1, I will explore the mechanisms by which this factor regulates the replication of the YFV
vaccine strain YFV-17D in vitro as well as the host and virus determinants that govern such regulation. In Aim
2, I will determine the role of this factor on the replication of a virulent YFV strain, YFV-Asibi, as well as of other
flaviviruses of interest such as ZIKV and DENV. I will also seek to explore the role of this factor using more
relevant cell culture system such as primary human hepatocytes by using specific inhibitor of this factor. In Aim
3, I will use a humanized mouse model I recently developed and that is permissive to YFV infection to evaluate
the role of this factor on YFV-Asibi and YFV-17D replication in vivo, by treating mice with specific inhibitor of the
identified host factor. Altogether, my strong expertise in studying YFV virus in vitro and in vivo, combined with
the different viral tracking tools and in vivo models I have previously developed, position me very well to conduct
the proposed research. This research could provide novel avenues for the specific treatment of YFV infection
and enhance our understanding of the host-pathogen interactions that define flavivirus pathogenicity. This K22
Career Transition Award will help me achieve my scientific and career goals, which consist of transitioning toward
an independent assistant professor position and establishing an independent NIH-funded research program
aiming at elucidating the mechanisms of flavivirus pathogenicity.
项目摘要/摘要
黄热病病毒(YFV)、寨卡病毒(ZIKV)或登革热病毒(DENV)等黄病毒是导致
全球的健康和经济问题。YFV是黄病毒属的典型成员,也是
第一种已被鉴定的人类致病病毒。尽管已经开发出了一种非常有效的疫苗
20世纪30年代的S,YFV至今仍代表着一种真正的艺术。最近在安哥拉和巴西爆发的疫情,在过去两年里,
发生在疫苗接种覆盖率较低的地区。这些死灰复燃的事件体现了这种威胁,并
强调需要保护全世界估计有4亿至5亿人。面对一个意义重大的
疫苗短缺,现在在疫苗接种活动中使用部分剂量的疫苗,尽管没有/受到限制
长期保护的证据,因此强调迫切需要制定新的战略来
临床管理未来的YFV暴发。我们对YFV体外和体内感染周期的了解是
极其有限,最终阻碍了治疗YFV感染的特定疗法的开发,如
目前没有可用的。我最近在人类细胞中发现了一种新的YFV感染宿主调控因子,即
在体外有效地感染和复制YFV所需的。由于它不在老鼠体内表达,这个因子也可能
对YFV的人类/灵长类特异性趋向性有贡献。基于一组可靠的初步数据,我
假设该因子通过与病毒直接结合来调节RNA复制或蛋白质翻译
元素。在目标1中,我将探索该因子调节YFV复制的机制
疫苗株YFV-17D在体外以及管理这种调控的宿主和病毒决定因素。在AIM
2,我将确定这个因子在YFV强毒株YFV-Asibi以及其他病毒株复制中的作用
感兴趣的黄病毒,如ZIKV和DENV。我还将使用更多的信息来探索这个因素的作用
相关细胞培养体系,如原代人肝细胞,使用该因子的特异性抑制物。在AIM
3、我将使用我最近开发的人源化小鼠模型,它允许YFV感染来评估
该因子对YFV-ASIBI和YFV-17D体内复制的影响
已确定的主机因素。总之,我在体外和体内研究YFV病毒方面的强大专业知识,结合
我之前开发的不同的病毒跟踪工具和体内模型,使我非常适合进行
建议的研究。本研究为YFV感染的特异性治疗提供了新的途径。
并加强我们对定义黄病毒致病性的宿主-病原体相互作用的理解。这款K22
职业过渡奖将帮助我实现我的科学和职业目标,其中包括向
一个独立的助理教授职位,并建立一个由国立卫生研究院资助的独立研究项目
目的阐明黄病毒的致病机制。
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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Florian Douam的其他文献
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{{ truncateString('Florian Douam', 18)}}的其他基金
Characterization of a human-specific positive regulator of flavivirus infection
黄病毒感染的人类特异性正调节因子的表征
- 批准号:
9721324 - 财政年份:2021
- 资助金额:
$ 10.64万 - 项目类别:
Characterization of a human-specific positive regulator of flavivirus infection
黄病毒感染的人类特异性正调节因子的表征
- 批准号:
10843473 - 财政年份:2021
- 资助金额:
$ 10.64万 - 项目类别:
Defining the Impact of Per/Polyfluoroalkyl Substance Exposure on Susceptibility to SARS-CoV-2 Infection and Disease
确定全氟烷基/多氟烷基物质暴露对 SARS-CoV-2 感染和疾病易感性的影响
- 批准号:
10362610 - 财政年份:2021
- 资助金额:
$ 10.64万 - 项目类别:
Defining the Impact of Per/Polyfluoroalkyl Substance Exposure on Susceptibility to SARS-CoV-2 Infection and Disease
确定全氟烷基/多氟烷基物质暴露对 SARS-CoV-2 感染和疾病易感性的影响
- 批准号:
10193236 - 财政年份:2021
- 资助金额:
$ 10.64万 - 项目类别:
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