Innate Immune Regulation of Intracellular Pathways Involved in Filovirus Budding
丝状病毒出芽涉及的细胞内途径的先天免疫调节
基本信息
- 批准号:8635498
- 负责人:
- 金额:$ 24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-12-01 至 2015-11-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAntiviral AgentsAttentionBiological AssayBioterrorismCategoriesCell SeparationCell membraneCellsCo-ImmunoprecipitationsComplexDNA VirusesDataDefense MechanismsDevelopmentDiseaseEventFamilyFilopodiaFiloviridaeFilovirusFluorescenceFluorescence Resonance Energy TransferFunding MechanismsFutureGenesHost DefenseHumanImageImaging TechniquesImmuneImmune Response GenesImmune responseImmune systemIn VitroInfectionInterferonsInvadedLaboratoriesLifeMapsMediatingMembraneMicrofilamentsMicroscopyMono-SMorphologyNational Institute of Allergy and Infectious DiseaseNaturePathway interactionsPeptide HydrolasesProcessProductionProlineProteinsRNA VirusesRecruitment ActivityRegulationReportingRoleSiteSmall Interfering RNAStagingSyndromeSystemTestingUbiquitinationVaccinesVacuolar Protein SortingViralViral Matrix ProteinsVirionVirusVirus DiseasesVirus-like particlebasecell motilitycombatfightinginnovationmortalitymutantnovelnovel strategiesnovel therapeuticspathogenpolymerizationprotein complexpublic health relevancesmall hairpin RNAtransmission processviral RNA
项目摘要
Ebola (EBOV) and Marburg (MARV) are enveloped, negative-sense RNA viruses belonging to the family
Filoviridae. Neither vaccines nor antivirals are currently available to combat these dangerous NIAID Category
A pathogens, which cause hemorrhagic syndromes with high mortality rates in humans. Our laboratory focuses
on the mechanisms by which filoviruses "hijack" host proteins to regulate budding, and how the innate immune
system counteracts such interactions to block virus egress. Despite the well known role of EBOV VP40 in
promoting late stages of virus budding, its potential contributions to early budding stages (e.g. cytoskeletal
remodeling and initial bud protrusion) are virtually unknown. Here, we will explore an unanticipated VP40-host
interaction that may promote early stages of viral budding and its potential regulation by the innate immune
system. Notably, we have identified host IQGAP1 as an interacting partner for EBOV VP40. IQGAP1 is a
multidomain protein that orchestrates the formation of protein complexes involved in regulating cell motility,
actin filament assembly, and filopodia and lamellipodia formation. Intriguingly, IQGAP1 possesses a WW-
domain capable of interacting with a PPxY type L-domain of EBOV VP40, and our preliminary results using
siRNA demonstrate that IQGAP1 is required for efficient egress of VP40 virus-like particles (VLPs). Based on
these data, we will first test the hypothesis that EBOV VP40 L-domains sequentially recruit IQGAP1 via its
WW-domain to initiate early budding events, followed by host Nedd4 and/or Tsg101 to facilitate late stage
virus-cell separation (Aim 1). Importantly, IQGAP1 has been implicated as a target of the IFN-stimulated innate
immune response that provides a critical first line of defense against invading pathogens. Indeed, interferon
stimulated gene-15 (ISG15) is an innate immune response gene which has garnered recent attention due to its
broad-range of antiviral activity against a plethora of pathogens including DNA and RNA viruses. As our
preliminary results support the hypothesis that IQGAP1 promotes EBOV VLP budding, we hypothesize that
ISGylation of host IQGAP1 by ISG15 may disrupt VP40-IQGAP1 complexes, thereby contributing to the
subsequent decrease in functional VP40-Nedd4 and/or VP40-Tsg101 interactions required for budding. This
unique interplay between host innate immune defenses and viral encoded factors that regulate the budding
process will be explored in Aim 2. If our hypotheses are correct, these studies will: 1) challenge the current
paradigm that viral L-domain motifs function only at late steps of virus budding, 2) identify novel, functional
interactions between EBOV VP40 and host proteins/pathways involved in membrane protrusion, filopodia
formation, and/or actin cytoskeletal remodeling that contribute to early budding events, and 3) reveal new host
innate immune mechanisms that regulate budding of high priority, emerging pathogens.
埃博拉病毒(EBOV)和马尔堡病毒(MARV)是属于该科的包膜负义RNA病毒
项目成果
期刊论文数量(0)
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RONALD N HARTY其他文献
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{{ truncateString('RONALD N HARTY', 18)}}的其他基金
Role of Host Filamin Proteins in Regulating Filovirus Entry and Egress
宿主细丝蛋白在调节丝状病毒进入和排出中的作用
- 批准号:
10644499 - 财政年份:2023
- 资助金额:
$ 24万 - 项目类别:
Development of Host- Oriented Therapeutics Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),
针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的面向宿主的疗法的开发,
- 批准号:
10688262 - 财政年份:2022
- 资助金额:
$ 24万 - 项目类别:
Development of Host- Oriented Therapeutics Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),
针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的面向宿主的疗法的开发,
- 批准号:
10545109 - 财政年份:2022
- 资助金额:
$ 24万 - 项目类别:
Role of Host Angiomotin as a Central Regulator of Filovirus Egress and Dissemination
宿主血管动蛋白作为丝状病毒排出和传播的中央调节剂的作用
- 批准号:
10380684 - 财政年份:2021
- 资助金额:
$ 24万 - 项目类别:
Role of Host Angiomotin as a Central Regulator of Filovirus Egress and Dissemination
宿主血管动蛋白作为丝状病毒排出和传播的中央调节剂的作用
- 批准号:
10217843 - 财政年份:2021
- 资助金额:
$ 24万 - 项目类别:
Modular Domains of Host Proteins Regulate Filovirus Maturation
宿主蛋白的模块化结构域调节丝状病毒成熟
- 批准号:
9517218 - 财政年份:2018
- 资助金额:
$ 24万 - 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
- 批准号:
10257889 - 财政年份:2018
- 资助金额:
$ 24万 - 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
- 批准号:
10368115 - 财政年份:2018
- 资助金额:
$ 24万 - 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
- 批准号:
10599837 - 财政年份:2018
- 资助金额:
$ 24万 - 项目类别:
DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS AGAINST RNA VIRUSES
针对 RNA 病毒的小分子疗法的开发
- 批准号:
8903846 - 财政年份:2015
- 资助金额:
$ 24万 - 项目类别:
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