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The natural killer cell response against mouse cytomegalovirus infection

自然杀伤细胞对小鼠巨细胞病毒感染的反应

基本信息

批准号：
10189486
负责人：
Joseph Chai-Yuen Sun
金额：
$ 53.3万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-18 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189486
关键词：
ATG3 gene Activated Natural Killer Cell Address Antiviral Agents Antiviral Response Apoptosis Autophagocytosis BNIP3L gene Binding Binding Sites Biological Biology Cancer Patient Cell Compartmentation Cell Cycle Cell Survival Cells Clinical Clonal Expansion Communicable Diseases Cytomegalovirus Cytomegalovirus Infections DNA Binding DNA Binding Domain DNA sequencing Data Defect Development Disease Effector Cell Epigenetic Process Exhibits Family Family member Funding Gene Targeting Generations Genes Genetic Transcription Goals Grant Growth Health Helix-Turn-Helix Motifs High-Throughput RNA Sequencing Host Defense Human IFN consensus sequence binding protein IRF1 gene Immune Immune system Immunization Immunocompromised Host Immunologic Memory Immunoprecipitation Individual Infection Inflammatory Innate Immune System Interleukin-12 Investigation Knockout Mice Lead Life Lymphocyte Mass Spectrum Analysis Measures Mediating Memory Metabolic Metabolism Mitochondria Modeling Molecular Monkeys Murid herpesvirus 1 Mus Natural Killer Cells Newborn Infant Pathway interactions Pattern Phase Play Process Proteomics Reporter Rest Role STAT4 gene STAT4 protein System Testing Therapeutic Transcription Factor AP-1 Transcriptional Regulation Transgenic Mice Transgenic Organisms Transplant Recipients United States National Institutes of Health Virus Virus Diseases Winged Helix arm base chromatin immunoprecipitation comparative conditional knockout cytokine epigenetic profiling experimental study genomic locus member memory recall novel pathogen programs response transcription factor transcriptome transcriptomics

项目摘要

Project Summary Natural killer (NK) cells constitute an important arm of the host immune system that detects and eliminates virus-infected cells. Newborns and immunocompromised patients lack NK cells and are extremely susceptible to viral infection, and in particular, human cytomegalovirus (HCMV) can cause severe health complications or be life-threatening in these individuals. Mouse cytomegalovirus (MCMV) is an accurate and robust model for HCMV infection, and represents a good system to study antiviral NK cell responses. Using MCMV infection in mice, we have discovered that NK cells possess novel adaptive immune features such as clonal expansion and long-lived memory. From the funding in the initial R01 period, our lab has uncovered many of the cellular and molecular mechanisms underlying NK cell memory. Our long-term goals are to understand the general biology of NK cells and the molecular basis by which these powerful effector cells can mediate protection against pathogen invasion. To this end, we have recently identified a novel role for the transcription factor IRF8 in the NK cell response against MCMV infection. Based on this exciting preliminary data, our current R01 renewal proposes to use a newly-generated transgenic mouse where Irf8 is specifically ablated in NK cells to study the impact of this transcription factor in antiviral responses. In Aim 1, we will perform epigenetic profiling of activated NK cells to determine how IRF8-mediated NK cell expansion and effector function are controlled following MCMV infection. In Aim 2, we will identify the binding partners and gene targets of IRF8 in antiviral NK cells using proteomic and transcriptomic analyses, respectively. In Aim 3, we will measure mitochondrial health and metabolism in antiviral NK cells to investigate the mechanisms behind IRF8-mediated survival of effector and memory NK cells during the contraction phase following MCMV clearance. Together, the studies in this R01 renewal will not only advance our understanding of the transcriptional mechanisms whereby NK cells contribute to host defense during viral infection, but also establish novel clinical paradigms for how the NK cell compartment may be harnessed for immunization and therapeutic strategies against infectious disease.

项目概要自然杀伤 (NK) 细胞是宿主免疫系统的重要组成部分，检测并消除病毒感染的细胞。新生儿和免疫功能低下的患者缺乏NK细胞，极易受到病毒感染，尤其是人类巨细胞病毒 (HCMV) 可导致严重的健康并发症或危及生命这些人。小鼠巨细胞病毒 (MCMV) 是一种准确且稳健的模型 HCMV 感染，代表了研究抗病毒 NK 细胞反应的良好系统。通过对小鼠进行 MCMV 感染，我们发现 NK 细胞具有新的适应性免疫特征，例如克隆扩张和长期记忆。从在最初的 R01 时期的资金支持下，我们的实验室发现了许多细胞和 NK 细胞记忆的分子机制。我们的长期目标是了解 NK 细胞的一般生物学以及这些细胞的分子基础强大的效应细胞可以介导针对病原体入侵的保护。为此，我们最近发现了转录因子 IRF8 在 NK 细胞中的新作用针对 MCMV 感染的反应。基于这些令人兴奋的初步数据，我们目前 R01更新建议使用新产生的转基因小鼠，其中Irf8是在 NK 细胞中专门消除，以研究该转录因子在抗病毒中的影响回应。在目标 1 中，我们将对活化的 NK 细胞进行表观遗传分析，以确定如何控制 IRF8 介导的 NK 细胞扩增和效应器功能 MCMV 感染后。在目标 2 中，我们将识别结合伙伴和基因使用蛋白质组和转录组分析确定抗病毒 NK 细胞中 IRF8 的靶标，分别。在目标 3 中，我们将测量抗病毒药物中的线粒体健康和新陈代谢 NK 细胞研究 IRF8 介导的效应细胞存活背后的机制 MCMV 清除后收缩期的记忆 NK 细胞。在一起， R01 更新中的研究不仅将增进我们对转录的理解 NK 细胞在病毒感染期间有助于宿主防御的机制，而且为如何利用 NK 细胞区室建立新的临床范例针对传染病的免疫和治疗策略。