Adenovirus manipulation of cellular chromatin to overcome host responses
腺病毒操纵细胞染色质以克服宿主反应
基本信息
- 批准号:10238103
- 负责人:
- 金额:$ 54.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-24 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenovirus InfectionsAdenovirus ProteinAdenovirusesAntiviral AgentsAntiviral ResponseAppearanceArchitectureBindingBiochemicalBiological ModelsCell NucleusCell physiologyCellsChIP-seqChromatinChromatin StructureCore ProteinDNADNA BindingDNA DamageDNA VirusesDataDiseaseEffectivenessEnterobacteria phage P1 Cre recombinaseEvolutionExcisionGene DeliveryGene ExpressionGenetic TranscriptionGenomeGenomicsGoalsHMGB1 geneHealthHistonesHost DefenseHumanImmune responseImmunoblottingInfectionInflammatoryInnate Immune ResponseIntegration Host FactorsInterferon ActivationInterferonsKnowledgeLeadMajor Core ProteinMalignant NeoplasmsModificationMolecularMutationNatureNucleic AcidsNucleosomesOncolyticOutcomePhysical condensationPlaque AssayPlayProductionProteinsProteomicsPublic HealthQuantitative Reverse Transcriptase PCRResourcesRoleSignal TransductionStimulusSystemTestingTherapeuticVaccinationViralViral Core ProteinsViral GenesViral GenomeViral PackagingViral ProteinsVirionVirusVirus Diseasesdesignexperimental studygenome-widehuman DNAimprovednovelparticlepathogenprotein expressionprotein functionrecruitresponsesensortoolvectorviral DNA
项目摘要
PROJECT SUMMARY
The need to evade antiviral immune responses has driven evolution of viral strategies to manipulate host cell
chromatin, to control gene expression and subvert cellular defenses. Adenoviruses are ubiquitous viruses that
have provided both important model systems for understanding fundamental cellular processes, as well as
vectors for therapeutic purposes. Infections by Adenovirus and derived vectors elicit strong innate immune
responses, which impact both the course of disease and their effectiveness as vectors for gene delivery and
vaccination. Therefore understanding viral proteins that subvert host responses is important for treating
infections and improving therapeutic vector applications. Here we focus on Adenovirus protein VII, the major
core protein that was previously thought to function exclusively for packaging viral genomes. We discovered
that protein VII has unexpected roles on both viral and host genomes during Adenovirus infection. The long-
term goal of this project is to decipher how this histone-like viral protein overcomes innate host responses and
promotes production of infectious viral progeny. We recently showed that protein VII binds DNA and
nucleosomes, possesses post-transcriptional modifications (PTMs) analogous to histones, and accumulates in
chromatin during infection. We demonstrated that protein VII can alter the composition of host proteins
associated with viral genomes in the nuclei of infected cells, and also sequesters host factors in cellular
chromatin. Our central hypothesis is that Adenovirus protein VII mimics histones as part of an insidious
strategy that manipulates both viral and cellular chromatin to subvert innate host responses. This novel
hypothesis has been formulated on the basis of extensive preliminary data produced in our lab with new tools
we have generated to study how protein VII is necessary and sufficient to counter cellular immune responses.
The two integrated Specific Aims are designed to test our hypothesis by studying functions of protein VII on
viral and cellular genomes. Aim 1 will define functions of protein VII on the viral genome during infection.
Biochemical and molecular experiments will address how protein VII exploits host machinery to promote
production of infectious progeny. Aim 2 will examine the impacts of protein VII on cellular chromatin and
genome architecture. Genomic and cellular approaches will determine how association of protein VII with
cellular proteins and the chromatinized genome serves to counteract antiviral host responses. We have
assembled an interdisciplinary collaborative team to determine this core viral histone-like protein subverts
cellular innate immune responses in a project that has broader implications for understanding how viruses elicit
changes in chromatin to overcome host defenses.
项目摘要
逃避抗病毒免疫应答的需要已经推动了病毒策略的进化,以操纵宿主细胞,
染色质,控制基因表达和破坏细胞防御。腺病毒是普遍存在的病毒,
为理解基本细胞过程提供了重要的模型系统,
用于治疗目的的载体。腺病毒及其衍生载体的感染可引起强烈的先天性免疫
反应,影响疾病的过程和它们作为基因传递载体的有效性,
预防针因此,了解破坏宿主反应的病毒蛋白对于治疗
感染和改善治疗载体应用。在这里,我们重点关注腺病毒蛋白VII,主要
核心蛋白,以前被认为专门用于包装病毒基因组。我们发现
在腺病毒感染期间,蛋白VII在病毒和宿主基因组中都具有意想不到的作用。很长的-
该项目的长期目标是破译这种组蛋白样病毒蛋白如何克服先天宿主反应,
促进感染性病毒后代的产生。我们最近发现,蛋白质VII结合DNA,
核小体,具有类似于组蛋白的转录后修饰(PTM),并在细胞核中积累。
染色质在感染过程中。我们证明了蛋白VII可以改变宿主蛋白质的组成
与感染细胞核中的病毒基因组相关,并且还在细胞内隔离宿主因子。
染色质我们的中心假设是腺病毒蛋白VII模拟组蛋白,作为一种潜在的
操纵病毒和细胞染色质以破坏先天宿主反应的策略。这本小说
在我们实验室使用新工具产生的大量初步数据的基础上,
我们已经产生了研究蛋白质VII是如何必要和足够的对抗细胞免疫反应。
这两个整合的特异性目的旨在通过研究蛋白VII的功能来验证我们的假设,
病毒和细胞基因组。目标1将定义感染期间病毒基因组上蛋白VII的功能。
生物化学和分子实验将解决蛋白质VII如何利用宿主机制促进
感染性后代的产生。目的2将研究蛋白VII对细胞染色质的影响,
基因组结构基因组学和细胞学方法将确定蛋白质VII与
细胞蛋白质和染色质化的基因组用于抵消抗病毒宿主应答。我们有
组建了一个跨学科的合作团队,以确定这种核心的病毒组蛋白样蛋白颠覆
在一个项目中,细胞先天免疫反应对理解病毒如何引起
改变染色质来克服宿主的防御。
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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Matthew D. Weitzman其他文献
Recruitment of wild-type and recombinant adeno-associated virus into adenovirus replication centers
将野生型和重组腺相关病毒招募到腺病毒复制中心
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:5.4
- 作者:
Matthew D. Weitzman;K. Fisher;James M. Wilson - 通讯作者:
James M. Wilson
Probing condensate microenvironments with a micropeptide killswitch
用微肽杀手探针探测冷凝液微环境
- DOI:
10.1038/s41586-025-09141-5 - 发表时间:
2025-06-04 - 期刊:
- 影响因子:48.500
- 作者:
Yaotian Zhang;Ida Stöppelkamp;Pablo Fernandez-Pernas;Melanie Allram;Matthew Charman;Alexandre P. Magalhaes;Melanie Piedavent-Salomon;Gregor Sommer;Yu-Chieh Sung;Katrina Meyer;Nicholas Grams;Edwin Halko;Shivali Dongre;David Meierhofer;Michal Malszycki;Ibrahim A. Ilik;Tugce Aktas;Matthew L. Kraushar;Nadine Vastenhouw;Matthew D. Weitzman;Florian Grebien;Henri Niskanen;Denes Hnisz - 通讯作者:
Denes Hnisz
Interaction of wild-type and mutant adeno-associated virus (AAV) Rep proteins on AAV hairpin DNA
野生型和突变型腺相关病毒 (AAV) Rep 蛋白在 AAV 发夹 DNA 上的相互作用
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:5.4
- 作者:
Matthew D. Weitzman;S. R. Kyöstiö;Barrie J. Carter;R. Owens - 通讯作者:
R. Owens
A Tribute to Barrie Carter.
向巴里·卡特致敬。
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:4.2
- 作者:
A. Srivastava;Matthew D. Weitzman;S. Chatterjee;J. Engelhardt;R. Owens;Nick Muzyczka;Robin Ali - 通讯作者:
Robin Ali
Live Cell Fluorescence Correlation Spectroscopy with Real Time Photoactivation Feedback
- DOI:
10.1016/j.bpj.2012.11.3181 - 发表时间:
2013-01-29 - 期刊:
- 影响因子:
- 作者:
Matthew D. Weitzman;Chandran R. Sabanayagam;Kenneth L. van Golen - 通讯作者:
Kenneth L. van Golen
Matthew D. Weitzman的其他文献
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{{ truncateString('Matthew D. Weitzman', 18)}}的其他基金
Non-canonical chimeric proteins generated during Adenovirus infection
腺病毒感染期间产生的非典型嵌合蛋白
- 批准号:
10448505 - 财政年份:2021
- 资助金额:
$ 54.24万 - 项目类别:
Ubiquitination during infection with Mouse Adenovirus
小鼠腺病毒感染过程中的泛素化
- 批准号:
10152932 - 财政年份:2021
- 资助金额:
$ 54.24万 - 项目类别:
Non-canonical chimeric proteins generated during Adenovirus infection
腺病毒感染期间产生的非典型嵌合蛋白
- 批准号:
10312411 - 财政年份:2021
- 资助金额:
$ 54.24万 - 项目类别:
Ubiquitination during infection with Mouse Adenovirus
小鼠腺病毒感染过程中的泛素化
- 批准号:
10364682 - 财政年份:2021
- 资助金额:
$ 54.24万 - 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
- 批准号:
9886201 - 财政年份:2019
- 资助金额:
$ 54.24万 - 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
- 批准号:
10092100 - 财政年份:2019
- 资助金额:
$ 54.24万 - 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
- 批准号:
10359055 - 财政年份:2019
- 资助金额:
$ 54.24万 - 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
- 批准号:
9764127 - 财政年份:2019
- 资助金额:
$ 54.24万 - 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
- 批准号:
10571919 - 财政年份:2019
- 资助金额:
$ 54.24万 - 项目类别:
Adenovirus manipulation of cellular chromatin to overcome host responses
腺病毒操纵细胞染色质以克服宿主反应
- 批准号:
9979734 - 财政年份:2018
- 资助金额:
$ 54.24万 - 项目类别:
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