Dissecting immune surveillance to gammaherpesviruses

剖析对伽马疱疹病毒的免疫监视

• 批准号: 10686412
• 负责人: Edward J Usherwood
• 金额: $ 58.2万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686412
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Apoptosis; B-Cell Lymphomas; B-Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Immunity; Cellular Metabolic Process; Chronic; Data; Defect; Development; Disease; Electron Transport; Failure; Family; Gene Expression Profile; Generations; Genes; Glycolysis; Growth; HIV; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Immunity; Immunologic Deficiency Syndromes; Immunologic Surveillance; Immunotherapy; Impairment; Infection; Knowledge; Laboratories; Lead; Left; Lymphoma; Malignant Neoplasms; Mediating; Memory; Mental Depression; Metabolic; Metabolic Pathway; Mitochondria; Modeling; Molecular; Mus; Pathway interactions; Patients; Population; Predisposition; Pyruvate Kinase; Respiration; Rodent; Role; System; T cell differentiation; T cell regulation; T cell response; T-Lymphocyte; Testing; Transcription Repressor; Virus; Virus Diseases; Virus Latency; Virus Replication; Work; acute infection; chronic infection; design; experience; experimental study; gammaherpesvirus; genetically modified cells; improved; in vivo; insight; knock-down; latent infection; long term memory; metabolic rate; mitochondrial metabolism; mouse model; novel; pathogen; prevent; rational design; recruit; respiratory; response; restoration; single-cell RNA sequencing; transcription factor; transcriptomics

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.

由HIV引起的免疫缺陷的主要驱动力是T细胞的破坏，如果没有治疗的结果 在艾滋病中。细胞免疫的抑郁导致无法控制先前存在的病毒感染，例如 人类γ掌病毒：爱泼斯坦 - 巴尔病毒和卡波西相关的 疱疹病毒。在某些艾滋病患者中，由于无法控制病毒感染，这会导致严重疾病 细胞。疾病是在没有病毒的情况下引起潜在感染的B细胞感染的结果 复制。以前的工作表明，内存CD8 T细胞响应是最重要的组成部分 免疫监视，可控制健康患者的潜在感染细胞。因此更深入地理解 CD8 T细胞介导的免疫监测可以帮助我们了解艾滋病患者的这种反应如何失败， 促进制定恢复免疫监视的策略，以防止γ掌病毒相关 疾病。该提议将基于新颖的发现，即BTB-ZF家庭转录抑制剂ZBTB20是 对鼠γγ病毒-68（MHV-68）的有效免疫监测至关重要。这种啮齿动物病毒 事实证明，这是病毒免疫相互作用的绝佳模型，概括了许多免疫 用于控制与艾滋病相关的伽马病毒的机制。初步数据显示没有 ZBTB20可防止具有效应子 /效应器记忆转录签名的细胞产生。此外 在缺乏ZBTB20缺乏的CD8 T细胞中，糖酵解和线粒体代谢的速率异常升高， 表明ZBTB20在调节适用于分化的免疫代谢状态方面的重要作用 T细胞的状态。这很关键，因为很明显，T细胞的代谢状态是 与记忆细胞的区分，但对长期所需的代谢状态知之甚少 免疫监视。我们的转录组数据识别糖酵解和线粒体呼吸道中的关键基因 在没有ZTBTB20的情况下升高的途径。我们将测试这些基因的失调是否导致 免疫监测的损耗，以及基因敲低恢复适当的T细胞分化和 免疫代谢。进一步的实验测试了ZBTB20为防护所需的程度 缺乏内源性T细胞免疫的小鼠中与γ掌病毒感染相关的疾病，以模仿 艾滋病定义免疫缺陷。这些参数还使用T细胞进行了基因修改为 恢复效应子记忆分化或归一化代谢率。总而言之，意义是 对有效免疫监视所需的机械理解 与艾滋病相关的病原体。有了这些知识，我们可以设计改进的基于免疫的疗法 预防艾滋病患者严重疾病。