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.

艾滋病毒导致免疫缺陷的一个主要原因是T细胞的破坏，如果不加以治疗，就会导致这种结果 在艾滋病方面。细胞免疫抑制导致无法控制先前存在的病毒感染，例如 人类伽玛疱疹病毒感染：爱泼斯坦-巴尔病毒和卡波西肉瘤相关 疱疹病毒。在一些艾滋病患者中，由于未能控制病毒感染，这会导致严重的疾病 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潜伏感染 复制。以往的研究表明，记忆中CD8 T细胞反应是 控制健康患者体内潜伏感染细胞的免疫监测。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是如何失败的， 促进制定战略，以恢复免疫监测，以预防伽马疱疹病毒相关 疾病。这一建议将建立在BTB-ZF家族转录抑制因子Zbtb20是 对有效免疫监测小鼠伽马疱疹病毒-68(MHV-68)至关重要。这种啮齿动物病毒 已被证明是病毒-免疫相互作用的优秀模型，概括了许多免疫 用于控制艾滋病相关伽马疱疹病毒的机制。初步数据显示， Zbtb20阻止具有效应器/效应器记忆转录签名的细胞的产生。此外 在Zbtb20缺陷的CD8T细胞中，糖酵解和线粒体代谢率都异常升高， 提示Zbtb20在调节适宜分化的免疫代谢状态中起重要作用 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 分化为记忆细胞，但对长期所需的代谢状态知之甚少 免疫监视。我们的转录组数据确定了糖酵解和线粒体呼吸的关键基因 在没有Ztbtb20的情况下升高的通路。我们将测试这些基因的失调是否会导致 免疫监视的磨损，如果基因敲除恢复了适当的T细胞分化和 免疫新陈代谢。进一步的实验测试Zbtb20在多大程度上是保护 在缺乏内源性T细胞免疫的小鼠中与伽马疱疹病毒感染相关的疾病，以模仿 艾滋病--定义免疫缺陷。这些参数也是使用转基因T细胞进行测试的 恢复效应器记忆分化或使代谢率正常化。总而言之，它的意义在于 对针对一类重要病毒的有效免疫监测所需条件的机械理解 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来 预防艾滋病患者的严重疾病。