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.

HIV引起的免疫缺陷的一个主要驱动因素是T细胞的破坏，如果不及时治疗就会导致T细胞的破坏