Defining the Mechanisms of Epstein-Barr Virus Persistence and Recurrence
定义 Epstein-Barr 病毒持续存在和复发的机制
基本信息
- 批准号:10599350
- 负责人:
- 金额:$ 46.71万
- 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:2016-03-04 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdolescenceAdultApoptoticArchitectureB lymphocyte immortalizationB-Cell ActivationB-LymphocytesBAG3 geneBenignBiochemicalBiologicalBiologyCell Differentiation processCell Fate ControlCell LineageCell MaturationCell SurvivalCellsCellular Metabolic ProcessChromatinDataEpithelial CellsEpstein-Barr Virus latencyGene ExpressionGenesGenetic TranscriptionGoalsHerpesviridaeHumanHuman Herpesvirus 4ImmuneImmunoglobulin Class SwitchingImmunoglobulin-Secreting CellsIndividualInfectionInfectious MononucleosisLatent virus infection phaseLife Cycle StagesLinkLymphoid TissueLyticLytic VirusMCL1 geneMalignant NeoplasmsMediatingMemoryMemory B-LymphocyteMitochondriaModalityModelingMolecularMolecular ChaperonesMolecular ConformationNFKB2 geneOralOral cavityPRDM1 genePhenotypePlasma CellsPlasmablastPrimary InfectionProductivityProliferatingProteinsReactionRecurrenceRegulationResearchRestSalivaSamplingSignal TransductionStructure of germinal center of lymph nodeTestingTherapeuticTonsilViralViral GenesViral Load resultVirionVirusXBP1 geneYY1 Transcription Factorcell immortalizationin vivoinsightlatent infectionmimicrynovelperipheral bloodplasma cell differentiationprogramsreactivation from latencyrecruitsingle-cell RNA sequencingtranscription factortransmission processvirtual
项目摘要
ABSTRACT
Our ultimate goal to define the molecular mechanisms for EBV latency establishment and reactivation in the oral
cavity. In this proposal, we aim to characterize how EBV usurps B-cell maturation programs for cell survival and
the establishment of a continuum of cell states balancing latency-driven proliferation, differentiation, and lytic
reactivation. It is our central hypothesis that EBV establishes B-cell latent infection through mimicry of the
germinal center (GC) reaction and subsequently promotes a continuum of activation and differentiation that is
balanced to enable access to a cell state supporting lytic reactivation. We have formulated our central hypothesis
based on preliminary data including single-cell gene expression, chromatin conformation of tonsillar B cells and
EBV-immortalized cells as well as characterization of new spontaneously lytic strains of EBV. We found that
EBV latent infection promotes GC mimicry through temporal regulation of anti-apoptotic MCL-1 and BFL-1. Using
scRNA-seq of LCLs, we discovered a continuum of gene expression where NFB signaling/activation (e.g.
NFKB2, MYC, IRF8) is strongly anti-correlated with plasmablast differentiation (e.g. CD38, PRDM1, XBP1).
Furthermore, EBV lytic genes were expressed in cells most similar to the high differentiation state suggesting a
model whereby EBV-infected cells constantly sample this differentiated state to enable a switch to lytic
reactivation. Finally, using new strains of EBV we describe a paradigm of a persistent, spontaneous switch to
productive infection that is transient and reversible. Therefore, the rationale for this proposed research is that
understanding how EBV establishes latency and reactivates to productive infection provides insight into
therapeutic modalities to eliminate EBV-infected cells from the oral cavity. The underlying molecular circuitry
controlling these cell fate decisions may also provide important new information regarding the plasticity of B-cell
maturation states. We plan to test our central hypothesis and complete the objectives in this proposal through
the following three specific aims: i) to determine the molecular mechanisms by which EBV promotes B-cell
survival mimicking tonsillar B-cell maturation, ii) to define the underlying molecular circuitry supporting a novel
activation/differentiation continuum within individual EBV-immortalized B cells, and iii) to define the biochemical
and cell biological features of a newly described EBV recurrence phenotype in which latently infected cells
produce virions and return to their basal latent state.
抽象的
我们定义EBV潜伏期建立和重新激活的分子机制的最终目标
缓存。在此提案中,我们旨在表征EBV如何篡夺B细胞成熟计划,以用于细胞生存和
建立一个连续的细胞状态,平衡潜伏期驱动的增殖,分化和裂解
重新激活。我们的核心假设是,EBV通过模仿模仿建立B细胞潜在感染
生发中心(GC)反应,随后促进了激活和分化的连续性
平衡以使能够访问支持裂解重新激活的细胞状态。我们已经提出了中心假设
基于初步数据,包括单细胞基因表达,扁桃体B细胞的染色质构象和
EBV侵蚀性细胞以及EBV的新赞助商裂解菌株的表征。我们发现
EBV潜在感染通过抗凋亡MCL-1和BFL-1的临时调节促进GC模拟。使用
LCLS的SCRNA-SEQ,我们发现了基因表达的连续体,其中NFB信号传导/激活(例如,
NFKB2,MYC,IRF8)与浆膜分化非常抗相关(例如CD38,PRDM1,XBP1)。
此外,EBV裂解基因在与高分化状态最相似的细胞中表达
模型,通过该模型,EBV感染的单元不断采样了这种差异化状态以使转换为裂解
重新激活。最后,使用新的EBV菌株,我们描述了一个持续的,赞的范式
瞬时和可逆的生产感染。因此,这项拟议研究的理由是
了解EBV如何建立潜伏期并重新激活产品感染
从口腔中消除EBV感染的细胞的治疗方式。基础分子电路
控制这些细胞脂肪决策也可能提供有关B细胞可塑性的重要新信息
成熟状态。我们计划通过
以下三个特定目的:i)确定EBV促进B细胞的分子机制
生存模仿扁桃体B细胞的成熟,ii)定义支持新颖的基本分子电路
激活/分化在单个EBV侵蚀B细胞中继续进行,并在iii中定义生化
以及新描述的EBV复发表型的细胞生物学特征,其中潜在感染细胞
产生病毒并返回其基本潜在状态。
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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Micah A. Luftig其他文献
Micah A. Luftig的其他文献
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{{ truncateString('Micah A. Luftig', 18)}}的其他基金
Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas
定义和利用非霍奇金淋巴瘤中 EBV 感染细胞的异质性
- 批准号:
10706553 - 财政年份:2022
- 资助金额:
$ 46.71万 - 项目类别:
Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas
定义和利用非霍奇金淋巴瘤中 EBV 感染细胞的异质性
- 批准号:
10541348 - 财政年份:2022
- 资助金额:
$ 46.71万 - 项目类别:
Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis
剖析 EBV 和恶性疟原虫在地方性伯基特淋巴瘤发病机制中的作用
- 批准号:
10204966 - 财政年份:2019
- 资助金额:
$ 46.71万 - 项目类别:
Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis
剖析 EBV 和恶性疟原虫在地方性伯基特淋巴瘤发病机制中的作用
- 批准号:
10671667 - 财政年份:2019
- 资助金额:
$ 46.71万 - 项目类别:
Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis
剖析 EBV 和恶性疟原虫在地方性伯基特淋巴瘤发病机制中的作用
- 批准号:
10459337 - 财政年份:2019
- 资助金额:
$ 46.71万 - 项目类别:
Defining the Mechanisms of Epstein-Barr Virus Persistence and Recurrence
定义 Epstein-Barr 病毒持续存在和复发的机制
- 批准号:
10437789 - 财政年份:2016
- 资助金额:
$ 46.71万 - 项目类别:
Targeting Apoptosis and Immune Control of Epstein-Barr Virus Infected Tonsillar B Cells
针对 Epstein-Barr 病毒感染的扁桃体 B 细胞的凋亡和免疫控制
- 批准号:
9237256 - 财政年份:2016
- 资助金额:
$ 46.71万 - 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
- 批准号:
10663313 - 财政年份:2011
- 资助金额:
$ 46.71万 - 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
- 批准号:
8187400 - 财政年份:2011
- 资助金额:
$ 46.71万 - 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
- 批准号:
8843606 - 财政年份:2011
- 资助金额:
$ 46.71万 - 项目类别:
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