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Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection

小鼠巨细胞病毒感染期间自然杀伤细胞反应的转录机制

基本信息

批准号：
10382356
负责人：
Timothy E O'Sullivan
金额：
$ 45.35万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-06 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382356
关键词：
ATG3 gene Acquired Immunodeficiency Syndrome Activated Natural Killer Cell Adaptive Immune System Address Antigens Apoptosis Autophagocytosis Biological Assay Biological Process Cell Count Cell Cycle Cell Death Cell Proliferation Cell Survival Cells ChIP-seq Clinical Clonal Expansion Communicable Diseases Cytomegalovirus Cytomegalovirus Infections DNA sequencing Data Defect Dominant-Negative Mutation Excision Exhibits Foundations Frequencies Gene Targeting Generations Genes Genetic Transcription Genomics Goals Health Human Immune system Immunization Individual Infection Innate Immune System Knockout Mice Lead Life Lymphocyte Lymphocyte Function Macaca Malignant Neoplasms Measures Memory Metabolism Mitochondria Modeling Molecular Murid herpesvirus 1 Mus Natural Killer Cells Newborn Infant Organ Transplantation Pathway interactions Patients Pattern Phase Proliferating Property Protein Isoforms Quantitative Reverse Transcriptase PCR Regulatory Element Reporter Reporting Repression Risk Role Signal Transduction Specificity TP53 gene Testing Time Transgenic Mice Validation Viral Virus Virus Diseases Work cancer cell cdc Genes epidemiology study experimental study immunosuppressed in vivo mitochondrial metabolism next generation novel novel therapeutics novel vaccines response transcription factor transcriptome transcriptome sequencing vaccine strategy

项目摘要

Project Summary Natural killer (NK) cells are lymphocytes of the immune system that can detect and kill virally infected cells. Epidemiological studies have shown that immunosuppressed (e.g. cancer, organ transplant, AIDS) patients and newborns display an enhanced risk for health complications associated with human cytomegalovirus (HCMV) infection that can be life-threating. Previous work has shown that mouse cytomegalovirus (MCMV) infection in mice can accurately model HCMV infection, and demonstrated that NK cells are critical for the control of MCMV. Furthermore, NK cells have been shown to have properties of the adaptive immune system such as recall responses, antigen-specificity, and clonal expansion in mice, macaques, and humans. Although our work has made significant progress into elucidating how autophagy and mitophagy lead to the generation of memory NK cells and the survival of proliferating lymphocytes, the upstream regulatory elements of these fundamental biological processes remain poorly understood in lymphocytes in vivo. Our long-term goals seek to identify the relevant transcriptional signals that induce autophagy, mitophagy, and survival of memory NK cells following viral infection. In RNA-sequencing experiments, we have identified Trp73 (p73) as a transcription factor selectively enriched in memory NK cells following murine cytomegalovirus (MCMV) infection. Further experimental validation by qRT-PCR revealed that two dominant isoforms of Trp73 in mice (TAp73 and ΔNp73) display distinct temporal expression patterns in NK cells during MCMV infection. Importantly, the roles of p73 transcriptional isoforms in lymphocyte responses to viral infection in vivo are unknown. Our exciting preliminary findings suggest that ΔNp73 is transiently induced in effector NK cells and is required for clonal expansion and generation of memory NK cells. In contrast, TAp73 expression is sustained in effector and memory NK cells and is dispensable for effector NK proliferation, but critical for the survival and generation of memory NK cells. In Aim 1, we will determine whether TAp73 influences autophagic removal of dysfunctional mitochondria in NK cells to promote the survival of effector NK cells as they transition to memory cells using cutting-edge autophagy and metabolism assays. In Aim 2, we will determine whether ΔNp73 leads to the proliferation of effector NK cells through repression of p53 to shield NK cells from apoptosis or relieve cell cycle repression. In Aim 3, we will perform RNA and ChIP-sequencing experiments to determine the gene targets of p73 in effector NK cells using genomic analyses. In summary, the proposed studies included in this R01 proposal will contribute to our basic understanding of how primary cells induce mitophagy in vivo, while also contributing to novel clinical strategies to enhance the use of adaptive NK cell responses for immunization against infectious disease.

项目总结