The role of mammarenavirus defective interfering particles in protecting host fitness and the host-driven post-translational modifications that regulate their formation and function
The role of mammarenavirus defective interfering particles in protecting host fitness and the host-driven post-translational modifications that regulate their formation and function
批准号:
10514041
负责人:
Jason W. Botten
金额:
$54.39万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-08-19 至 2027-07-31
关键词:
AddressAlpha ParticlesAnimalsArenavirusBindingBunyaviralesCell physiologyCellsDefective VirusesDiseaseEcologyEngineeringEnsureEnvironmental ImpactFamilyGenerationsGoalsHumanImmune responseImmunityInfectionIntegration Host FactorsInvestigationKnowledgeLifeLigaseLinkLymphocytic choriomeningitis virusMaintenanceMapsModificationMolecularMusNaturePathogenesisPathway interactionsPhosphorylationPhosphotransferasesPolymerasePost-Translational Protein ProcessingProductionPropertyProtein Tyrosine KinaseProteinsProteomeRNA VirusesReagentRecombinantsRegulationResolutionRodentRoleSiteStudy modelsSystemTestingTimeUbiquitinationViralViral Matrix ProteinsViral PathogenesisViral ProteinsVirionVirusVirus DiseasesWorkZoonosesacute infectionchronic infectionfitnesshuman pathogenin vivoinnovationnovelparticlepathogenpathogenic virusplasma protein Zrecruitreverse geneticstooltraffickingtransmission processubiquitin-protein ligasevectorvirologyvirus host interaction
中文摘要
RNA病毒的关键发现,如双节,单链沙粒病毒家族,产生
50多年前,有缺陷的干扰颗粒(DIP)促使人们研究它们对病毒的贡献。
发病机制和宿主免疫。然而,许多基本问题仍然存在,包括
DIPs是如何被调节的,以及DIPs对病毒-宿主相互作用的贡献,包括DIPs的持续存在。
人畜共患病原体在其储存宿主。我们的总体目标是确定负责
调节沙粒病毒DIP生产,并询问DIP对储层适合性的影响。一个主要
了解DIP在病毒发病机制和疾病生态学中的真正作用的限制是缺乏工具
以调节实验系统中的DIP水平。我们最近发现LCMV使用不同的细胞
产生标准病毒颗粒与DIP的途径。利用反向遗传系统,我们发现
强大的宿主驱动的翻译后修饰(PTM),动态调节
感染性病毒颗粒与缺陷性病毒颗粒。这些研究使我们能够第一次,
不再产生DIP的沙粒病毒。我们的具体目标将是利用这些创新方法
和工具来1)定义宿主酪氨酸激酶和NEDD 4家族E3泛素连接酶
调节DIP的形成和功能,2)扩大我们可能影响DIP的沙粒病毒PTM的全球地图
生产,和3)将这些分子发现与建模持续性感染
啮齿动物宿主的感染和啮齿动物或偶然人类宿主的急性感染。大多数RNA病毒感染
动物产生DIP,这表明它们对这些病毒的维持至关重要
在自然界中。我们的研究结果将广泛适用于布尼亚病毒目以外。总的来说,
这些研究将为DIP生产的监管提供更大的解决方案,并首次回答,
DIP在病毒持久性中的作用。
英文摘要
The pivotal discovery of RNA viruses, like the bi-segmented, single-stranded arenavirus family, producing
defective interfering particles (DIPs) over 50 years ago prompted investigations on their contribution to viral
pathogenesis and host immunity. However, many basic questions remain, including the molecular basis for
how DIPs are regulated and the contribution of DIPs to virus–host interactions, including the persistence of
zoonotic pathogens in their reservoir host. Our overall goal is to identify the cellular machinery responsible for
regulating arenavirus DIP production and interrogate the impact DIPs have on reservoir fitness. A major
constraint to understanding the true role of DIPs in viral pathogenesis and disease ecology is the lack of tools
to modulate DIP levels in experimental systems. We recently discovered that LCMV uses divergent cellular
pathways to produce standard virus particles versus DIPs. Using reverse genetic systems, we identified
powerful host-driven post-translational modifications (PTMs) that dynamically regulate the production of
infectious versus defective viral particles. These studies enabled us to engineer, for the first time, recombinant
arenaviruses that no long produce DIPs. Our specific objectives will be to use these innovative approaches
and tools to 1) define the mechanism by which host tyrosine kinases and NEDD4 Family E3 ubiquitin ligases
regulate DIP formation and function, 2) expand our global map of arenavirus PTMs that may influence DIP
production, and 3) connect these molecular findings to pathogenesis studies modeling both persistent infection
of the rodent reservoir and acute infection of the rodent or incidental human host. Most RNA viruses that infect
animals produce DIPs, which suggests they are fundamentally important for the maintenance of these viruses
in nature. Our findings will be broadly applicable beyond the Bunyavirales order. Collectively, the completion of
these studies will provide greater resolution on the regulation of DIP production and answer, for the first time,
the role of DIP in viral persistence.
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The role of mammarenavirus defective interfering particles in protecting host fitness and the host-driven post-translational modifications that regulate their formation and function
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批准号:10687000
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项目类别:
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资助金额:$54.09万
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财政年份:2022
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负责人:Jason W. Botten
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依托单位:
A Novel Broad-spectrum Antiviral Agent
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批准号:10323057
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资助金额:$29.07万
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财政年份:2021
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负责人:Jason W. Botten
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依托单位:
A Novel Broad-spectrum Antiviral Agent
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批准号:10156116
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资助金额:$29.99万
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财政年份:2021
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负责人:Jason W. Botten
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依托单位:
Deep sequencing the lymphocytic choriomeningitis arenavirus quasispecies to identify and functionally validate the molecular signature ofdefective interfering particles
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批准号:10043049
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项目类别:
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资助金额:$24.88万
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财政年份:2020
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Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine
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批准号:10334565
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资助金额:$60.9万
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财政年份:2019
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依托单位:
Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine
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批准号:10570174
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项目类别:
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资助金额:$60.84万
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财政年份:2019
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负责人:Jason W. Botten
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依托单位:
Mechanisms of Protection and Durability for a Live Attenuated Tetravalent Dengue Vaccine
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批准号:10089397
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项目类别:
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资助金额:$61.16万
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财政年份:2019
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负责人:Jason W. Botten
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依托单位:
A human monoclonal antibody therapy for treatment of hantavirus cardiopulmonary syndrome
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批准号:10611715
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项目类别:
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资助金额:$100.0万
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财政年份:2017
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负责人:Jason W. Botten
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依托单位:
HANTAVIRUS AND ARENAVIRUS HOST-PATHOGEN INTERACTIONS
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批准号:8360777
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项目类别:
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资助金额:$24.85万
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财政年份:2011
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负责人:Jason W. Botten
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依托单位:
Identification of Novel Arenavirus Protein-Host Cellular Protein Interactions
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批准号:8077445
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项目类别:
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资助金额:$18.86万
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财政年份:2010
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负责人:Jason W. Botten
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依托单位:
HANTAVIRUS AND ARENAVIRUS HOST-PATHOGEN INTERACTIONS
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批准号:8167736
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项目类别:
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资助金额:$23.66万
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财政年份:2010
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负责人:Jason W. Botten
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依托单位:
Identification of Novel Arenavirus Protein-Host Cellular Protein Interactions
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批准号:7990173
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项目类别:
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资助金额:$22.71万
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财政年份:2010
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负责人:Jason W. Botten
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依托单位:
HANTAVIRUS AND ARENAVIRUS HOST-PATHOGEN INTERACTIONS
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批准号:7959822
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项目类别:
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资助金额:$23.62万
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财政年份:2009
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负责人:Jason W. Botten
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依托单位:
Therap Human Monoclonal Antibod for Treatment of Hantavirus Cardiopulmonary Syndr
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批准号:7097037
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项目类别:
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资助金额:$29.41万
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财政年份:2005
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负责人:Jason W. Botten
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依托单位:
Dynamics of arenavirus gene expression in vivo
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批准号:6799294
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项目类别:
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资助金额:$3.17万
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财政年份:2003
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负责人:Jason W. Botten
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依托单位:
Dynamics of arenavirus gene expression in vivo
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批准号:6691446
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项目类别:
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资助金额:$4.64万
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财政年份:2003
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负责人:Jason W. Botten
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依托单位:
Therap Human Monoclonal Antibod for Treatment of Hantavirus Cardiopulmonary Syndr
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项目类别:
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资助金额:$44.11万
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财政年份:--
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负责人:Jason W. Botten
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依托单位:
Therap Human Monoclonal Antibod for Treatment of Hantavirus Cardiopulmonary Syndr
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批准号:7632143
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项目类别:
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资助金额:$45.47万
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财政年份:--
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负责人:Jason W. Botten
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依托单位:
Therap Human Monoclonal Antibod for Treatment of Hantavirus Cardiopulmonary Syndr
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批准号:7558708
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项目类别:
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资助金额:$31.98万
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财政年份:--
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负责人:Jason W. Botten
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依托单位:
海外基金