Dissecting immune surveillance to gammaherpesviruses
Dissecting immune surveillance to gammaherpesviruses
批准号:
10468133
负责人:
Edward J Usherwood
金额:
$58.2万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-09-16 至 2025-08-31
关键词:
Acquired Immunodeficiency SyndromeAffectApoptosisB-Cell LymphomasB-LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCellsCellular ImmunityCellular Metabolic ProcessChronicDataDefectDevelopmentDiseaseElectron TransportFailureFamilyGene Expression ProfileGenerationsGenesGlycolysisGrowthHIVHerpesviridaeHerpesviridae InfectionsHumanHuman Herpesvirus 4Human Herpesvirus 8ImmuneImmunityImmunologic Deficiency SyndromesImmunologic SurveillanceImmunotherapyImpairmentInfectionKnowledgeLaboratoriesLeadLeftLymphomaMalignant NeoplasmsMediatingMemoryMental DepressionMetabolicMetabolic PathwayMitochondriaModelingMolecularMusPathway interactionsPatientsPopulationPyruvate KinaseRespirationRodentRoleSystemT cell differentiationT cell regulationT cell responseT-LymphocyteTestingTranscription RepressorVirusVirus DiseasesVirus LatencyVirus ReplicationWorkacute infectionchronic infectiondesignexperienceexperimental studygammaherpesvirusgenetically modified cellsimprovedin vivoinsightknock-downlatent infectionlong term memorymetabolic ratemitochondrial metabolismmouse modelnovelpathogenpreventrational designrecruitrespiratoryresponserestorationsingle-cell RNA sequencingtranscription factortranscriptomics
中文摘要
HIV引起的免疫缺陷的主要驱动因素是T细胞的破坏,如果不加以治疗,
艾滋病细胞免疫的抑制导致无法控制预先存在的病毒感染,例如
人类γ疱疹病毒:爱泼斯坦-巴尔病毒和卡波西肉瘤相关的
疱疹病毒在一些艾滋病患者中,由于未能控制病毒感染,
细胞疾病是B细胞感染的结果,B细胞在没有病毒的情况下具有潜伏感染
复制的先前的研究表明,记忆性CD 8 T细胞应答是免疫应答中最重要的组成部分。
控制健康患者中潜伏感染细胞的免疫监视。因此,更深入地了解
CD 8 T细胞介导的免疫监视可以帮助我们了解这种反应在艾滋病患者中是如何失败的,
促进制定恢复免疫监视的战略,
疾病该提议将建立在BTB-ZF家族转录抑制子Zbtb 20是一个新的发现的基础上。
对鼠γ疱疹病毒-68(MHV-68)的有效免疫监视至关重要。这种啮齿动物病毒
已被证明是一个很好的模型,病毒免疫相互作用,重演了许多免疫
用于控制艾滋病相关γ疱疹病毒的机制。初步数据显示,
Zbtb 20阻止具有效应子/效应子记忆转录特征的细胞的产生。此外
糖酵解和线粒体代谢的速率在Zbtb 20缺陷型CD 8 T细胞中异常升高,
表明Zbtb 20在调节适于分化的免疫代谢状态中的重要作用
T细胞的状态。这是至关重要的,因为很明显,T细胞的代谢状态是T细胞增殖的关键驱动因素。
但是,对于长期分化为记忆细胞所需的代谢状态知之甚少。
免疫监视我们的转录组数据确定了糖酵解和线粒体呼吸的关键基因
在没有Ztbtb 20的情况下升高的途径。我们将测试这些基因的失调是否会导致
如果基因敲减恢复了适当的T细胞分化,
免疫代谢进一步的实验测试了Zbtb 20对于保护免受
在缺乏内源性T细胞免疫的小鼠中与γ疱疹病毒感染相关的疾病,以模拟
艾滋病定义的免疫缺陷。这些参数也使用遗传修饰的T细胞进行测试,
恢复效应记忆分化或使代谢率正常化。综上所述,
对有效的免疫监视所需的机制的理解,对一类重要的
艾滋病相关病原体。有了这些知识,我们可以设计改进的免疫疗法,
预防艾滋病患者的严重疾病。
英文摘要
A primary driver of immune deficiency caused by HIV is the destruction of T cells, which if left untreated results
in AIDS. Depression of cellular immunity results in a failure to control pre-existing virus infections, such as
those by the human gammaherpesviruses: the Epstein-Barr virus and the Kaposi's sarcoma-associated
herpesvirus. In some AIDS patients this results in severe disease, due to a failure to control virus-infected
cells. Disease is a consequence of infection of B cells that harbor latent infection in the absence of virus
replication. Previous work has shown the memory CD8 T cell response is the most important component of
immune surveillance that controls latently infected cells in healthy patients. Therefore deeper understanding of
CD8 T cell-mediated immune surveillance can help us understand how this response fails in AIDS patients,
promoting development of strategies to restore immune surveillance to prevent gammaherpesvirus-associated
diseases. This proposal will build on the novel finding that the BTB-ZF family transcription repressor Zbtb20 is
essential for effective immune surveillance against murine gammaherpesvirus-68 (MHV-68). This rodent virus
has proven to be an excellent model for virus-immune interactions, recapitulating many of the immune
mechanisms used to control AIDS-relevant gammaherpesviruses. Preliminary data show the absence of
Zbtb20 prevents the generation of cells with an effector / effector memory transcriptional signature. In addition
rates of both glycolytic and mitochondrial metabolism were aberrantly elevated in Zbtb20-deficient CD8 T cells,
indicating an important role for Zbtb20 in regulating immunometabolic status appropriate for the differentiation
state of the T cell. This is critical, as it is clear that the metabolic state of the T cell is a critical driver of
differentiation to memory cells, but very little is known about the metabolic state required for long-term
immune surveillance. Our transcriptomic data identify key genes in glycolytic and mitochondrial respiratory
pathways that are elevated in the absence of Ztbtb20. We will test whether dysregulation of these genes leads
to attrition of immune surveillance, and if gene knockdown restores appropriate T cell differentiation and
immunometabolism. Further experiments test the extent to which Zbtb20 is necessary for protection from
disease associated with gammaherpesvirus infection in mice lacking endogenous T cell immunity, to mimic
AIDS-defining immunodeficiency. These parameters are also tested using T cells genetically modified to
restore effector memory differentiation or normalize metabolic rates. In summary, the significance is a
mechanistic understanding of what is required for effective immune surveillance against an important class of
AIDS-associated pathogen. Armed with this knowledge, we can design improved immune-based therapies to
prevent serious disease in AIDS patients.
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会议论文
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批准号:10654844
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资助金额:$48.37万
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财政年份:2022
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批准号:10686412
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资助金额:$58.2万
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依托单位:
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批准号:10264919
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批准号:9283333
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财政年份:2016
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批准号:8507830
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资助金额:$40.27万
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批准号:7626304
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资助金额:$35.29万
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批准号:8074125
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资助金额:$34.59万
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财政年份:2007
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T cell function in murine gammaherpesvirus infection
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批准号:8660592
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资助金额:$40.5万
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财政年份:2007
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T cell function in murine gammaherpesvirus infection
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批准号:8839129
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资助金额:$40.5万
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财政年份:2007
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负责人:Edward J Usherwood
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T cell function in murine gammaherpesvirus infection
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批准号:8485924
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资助金额:$28.52万
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财政年份:2007
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负责人:Edward J Usherwood
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依托单位:
T cell function in murine gammaherpesvirus infection
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批准号:7327546
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资助金额:$35.98万
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财政年份:2007
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T cell function in murine gammaherpesvirus infection
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批准号:7866468
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资助金额:$34.94万
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财政年份:2007
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依托单位:
T cell function in murine gammaherpesvirus infection
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批准号:9058977
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资助金额:$40.5万
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财政年份:2007
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负责人:Edward J Usherwood
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依托单位:
T cell function in murine gammaherpesvirus infection
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批准号:7436227
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资助金额:$35.29万
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Immune surveillance in murine gammaherpesvirus infection
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财政年份:2004
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依托单位:
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批准号:6862731
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项目类别:
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资助金额:$29.5万
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财政年份:2004
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负责人:Edward J Usherwood
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依托单位:
Immune surveillance in murine gammaherpesvirus infection
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批准号:8234136
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资助金额:$27.62万
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财政年份:2004
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负责人:Edward J Usherwood
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Immune surveillance in murine gammaherpesvirus infection
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批准号:6798453
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资助金额:$29.41万
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财政年份:2004
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负责人:Edward J Usherwood
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依托单位:
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批准号:7845532
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资助金额:$41.89万
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依托单位:
海外基金