Dissecting immune surveillance to gammaherpesviruses

剖析对伽马疱疹病毒的免疫监视

• 批准号: 10468133
• 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/10468133
• 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; 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.

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， 细胞疾病是在没有病毒的情况下潜伏感染的B细胞感染的结果 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。