IRF-1: a brake to limit gammaherpesvirus infection and pathogenesis
IRF-1:限制伽马疱疹病毒感染和发病机制的刹车
基本信息
- 批准号:10066315
- 负责人:
- 金额:$ 36.53万
- 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:2016-12-05 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAnimal ModelAnimalsApoptosisAttenuatedB cell differentiationB-Cell ActivationB-Cell LymphomasB-LymphocytesChronicCommunicable DiseasesDNADeveloped CountriesDevelopmentEnsureEnzymesFutureGene ExpressionGeneticGenetic PolymorphismGoalsHIV/HCVHelper-Inducer T-LymphocyteHepatitis B VirusHodgkin DiseaseHumanHuman Herpesvirus 4IRF1 geneImmune signalingImmunocompromised HostImmunologyIncidenceIndividualInfectionIntegration Host FactorsLeadLifeLinkLymphomaLymphomagenesisMalignant NeoplasmsMediatingMemory B-LymphocyteModelingMolecularPathogenesisPredisposing FactorProcessProtein KinaseReactionResearchRisk FactorsRoleSignal PathwaySignal TransductionStructure of germinal center of lymph nodeT-LymphocyteTestingTranslatingTumor Suppressor ProteinsViralVirusVirus Diseasesgammaherpesvirushuman diseaseinsightnovelpatient populationprogramsprotein kinase C betaresponsetranscription factor
项目摘要
PROJECT SUMMARY
Gammaherpesviruses establish life-long infection in a majority of humans worldwide and are
associated with the development of cancer, including B cell lymphomas. The intimate
relationship between gammaherpesviruses and B cell differentiation is directly linked to the
lymphomagenic capacity of these viruses. To ensure the establishment of long-term latency in
memory B cells, gammaherpesviruses drive a unique polyclonal germinal center reaction during
early infection. Germinal center reaction represents a stage of B cell differentiation that is
characterized by rapid division of activated B cells along with genetic instability driven by
enzymes that either induce DNA breaks or mutagenize DNA. It is not surprising that most
Epstein-Barr virus-driven B cell lymphomas originate from germinal center or post germinal
center B cells. This robust, gammaherpesvirus-stimulated germinal center reaction is transient
and returns to near-baseline levels in long-term infected hosts. Importantly, it is not clear what
attenuates gammaherpesvirus-driven germinal center reaction. We have identified Interferon
Regulatory Factor-1 (IRF-1) as the first host factor that specifically attenuates
gammaherpesvirus-driven germinal center reaction. Studies proposed here test the hypothesis
that IRF-1 is the critical host factor that attenuates gammaherpesvirus-driven expansion and
transformation of germinal center B cells throughout life-long infection. The proposed studies
will define IRF-1-mediated signaling changes that attenuate gammaherpesvirus-driven
expansion of germinal center response and the relative contributions of B- and T cell-intrinsic
functions of IRF-1 to this process. Further, proposed studies will develop a novel animal model
of gammaherpesvirus lymphomagenesis. Successful completion of the proposed studies will
offer insights into the tumor suppressor mechanisms of IRF-1 and generate novel animal
models that will be of value to infectious disease, immunology, and cancer fields.
项目概要
伽马疱疹病毒在全世界大多数人中造成终生感染,并且
与癌症(包括 B 细胞淋巴瘤)的发展有关。亲密的
伽马疱疹病毒和 B 细胞分化之间的关系直接与
这些病毒的致淋巴瘤能力。确保建立长期延迟
记忆B细胞,伽马疱疹病毒在过程中驱动独特的多克隆生发中心反应
早期感染。生发中心反应代表 B 细胞分化的一个阶段
其特征是激活的 B 细胞快速分裂以及由以下因素驱动的遗传不稳定性
诱导 DNA 断裂或诱变 DNA 的酶。毫不奇怪,大多数
EB 病毒驱动的 B 细胞淋巴瘤起源于生发中心或生发后
中心B细胞。这种强烈的、伽马疱疹病毒刺激的生发中心反应是短暂的
并在长期感染的宿主中恢复到接近基线水平。重要的是,目前还不清楚是什么
减弱伽马疱疹病毒驱动的生发中心反应。我们已经鉴定出干扰素
调节因子-1 (IRF-1) 作为第一个特异性减弱的宿主因子
伽马疱疹病毒驱动的生发中心反应。这里提出的研究测试了假设
IRF-1 是减弱伽马疱疹病毒驱动的扩张的关键宿主因子
生发中心 B 细胞在终生感染过程中的转化。拟议的研究
将定义 IRF-1 介导的信号变化,从而减弱伽玛疱疹病毒驱动的信号变化
生发中心反应的扩展以及 B 细胞和 T 细胞固有的相对贡献
IRF-1在此过程中发挥的作用。此外,拟议的研究将开发一种新型动物模型
伽马疱疹病毒淋巴瘤发生。成功完成拟议的研究将
深入了解 IRF-1 的肿瘤抑制机制并产生新的动物
对传染病、免疫学和癌症领域有价值的模型。
项目成果
期刊论文数量(21)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
T Cell-Intrinsic Interferon Regulatory Factor 1 Expression Suppresses Differentiation of CD4+ T Cell Populations That Support Chronic Gammaherpesvirus Infection.
T 细胞内在干扰素调节因子 1 表达抑制支持慢性伽玛疱疹病毒感染的 CD4 T 细胞群的分化。
- DOI:10.1128/jvi.00726-21
- 发表时间:2021
- 期刊:
- 影响因子:5.4
- 作者:Jondle,CN;Johnson,KE;Mboko,WP;Tarakanova,VL
- 通讯作者:Tarakanova,VL
Liver X Receptors Suppress Activity of Cholesterol and Fatty Acid Synthesis Pathways To Oppose Gammaherpesvirus Replication.
- DOI:10.1128/mbio.01115-18
- 发表时间:2018-07-17
- 期刊:
- 影响因子:6.4
- 作者:Lange PT;Schorl C;Sahoo D;Tarakanova VL
- 通讯作者:Tarakanova VL
Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection.
- DOI:10.1038/s41467-018-07492-4
- 发表时间:2018-11-28
- 期刊:
- 影响因子:16.6
- 作者:Xin G;Zander R;Schauder DM;Chen Y;Weinstein JS;Drobyski WR;Tarakanova V;Craft J;Cui W
- 通讯作者:Cui W
Innate immunity and alpha/gammaherpesviruses: first impressions last a lifetime.
- DOI:10.1016/j.coviro.2020.07.002
- 发表时间:2020-10
- 期刊:
- 影响因子:5.9
- 作者:Jondle CN;Tarakanova VL
- 通讯作者:Tarakanova VL
B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection.
B 细胞特异性表达共济失调毛细血管扩张突变蛋白激酶促进慢性伽马疱疹病毒感染。
- DOI:10.1128/jvi.01103-17
- 发表时间:2017
- 期刊:
- 影响因子:5.4
- 作者:Darrah,EricJ;Kulinski,JosephM;Mboko,WadzanaiP;Xin,Gang;Malherbe,LaurentP;Gauld,StephenB;Cui,Weiguo;Tarakanova,VeraL
- 通讯作者:Tarakanova,VeraL
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Vera L. Tarakanova其他文献
34 - Nitric Oxide Prevents Pancreatic P-Cell Apoptosis Via Inhibition of the DNA Damage Response
- DOI:
10.1016/j.freeradbiomed.2015.10.071 - 发表时间:
2015-10-01 - 期刊:
- 影响因子:
- 作者:
Bryndon J. Oleson;Katarzyna A. Broniowska;Aaron Naatz;Vera L. Tarakanova;John A. Corbett - 通讯作者:
John A. Corbett
Vera L. Tarakanova的其他文献
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{{ truncateString('Vera L. Tarakanova', 18)}}的其他基金
Gammaherpesvirus protein kinase: a master manipulator of the host during chronic infection.
伽玛疱疹病毒蛋白激酶:慢性感染期间宿主的主要操纵者。
- 批准号:
10518464 - 财政年份:2022
- 资助金额:
$ 36.53万 - 项目类别:
Gammaherpesvirus protein kinase: a master manipulator of the host during chronic infection.
伽玛疱疹病毒蛋白激酶:慢性感染期间宿主的主要操纵者。
- 批准号:
10651854 - 财政年份:2022
- 资助金额:
$ 36.53万 - 项目类别:
Gammaherpesvirus and IL-17: using host antibacterial defense to benefit chronic virus infection
伽玛疱疹病毒和 IL-17:利用宿主抗菌防御来有益于慢性病毒感染
- 批准号:
10470873 - 财政年份:2021
- 资助金额:
$ 36.53万 - 项目类别:
Gammaherpesvirus and IL-17: using host antibacterial defense to benefit chronic virus infection
伽玛疱疹病毒和 IL-17:利用宿主抗菌防御来有益于慢性病毒感染
- 批准号:
10283264 - 财政年份:2021
- 资助金额:
$ 36.53万 - 项目类别:
ATM and gammaherpesvirus infection: a precarious balance
ATM 和伽玛疱疹病毒感染:不稳定的平衡
- 批准号:
9278127 - 财政年份:2014
- 资助金额:
$ 36.53万 - 项目类别:
ATM and gammaherpesvirus infection: a precarious balance
ATM 和伽玛疱疹病毒感染:不稳定的平衡
- 批准号:
9064721 - 财政年份:2014
- 资助金额:
$ 36.53万 - 项目类别:
ATM and gammaherpesvirus infection: a precarious balance
ATM 和伽玛疱疹病毒感染:不稳定的平衡
- 批准号:
8789294 - 财政年份:2014
- 资助金额:
$ 36.53万 - 项目类别:
The role of gammaherpesvirus protein kinase in lytic and latent infection
伽马疱疹病毒蛋白激酶在溶解性和潜伏性感染中的作用
- 批准号:
8132757 - 财政年份:2010
- 资助金额:
$ 36.53万 - 项目类别:
Regulation of gHV68-induced B cell proliferation
gHV68 诱导的 B 细胞增殖的调节
- 批准号:
6936276 - 财政年份:2005
- 资助金额:
$ 36.53万 - 项目类别:
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