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

• 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
• 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

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.

项目摘要 自然杀伤（NK）细胞构成宿主免疫系统的重要分支， 检测并清除感染病毒的细胞。新生儿和免疫功能低下患者 缺乏NK细胞，对病毒感染极其敏感，特别是人 巨细胞病毒（HCMV）可引起严重的健康并发症或危及生命， 这些人。小鼠巨细胞病毒（MCMV）是一种准确和稳健的模型， HCMV感染，并且代表了研究抗病毒NK细胞应答的良好系统。 使用MCMV感染小鼠，我们发现NK细胞具有新的 适应性免疫功能，如克隆扩张和长寿命记忆。从 在最初的R01阶段，我们的实验室已经发现了许多细胞， 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。为此目的， 我们最近发现了转录因子IRF8在NK细胞中的新作用， 对MCMV感染的反应。根据这些令人兴奋的初步数据，我们目前的 R01更新建议使用新产生的转基因小鼠，其中Irf8是 在NK细胞中特异性消融，以研究这种转录因子在抗病毒 应答在目标1中，我们将对活化的NK细胞进行表观遗传学分析， 确定IRF 8介导的NK细胞扩增和效应器功能是如何控制的 MCMV感染后。在目标2中，我们将确定结合伴侣和基因 使用蛋白质组学和转录组学分析的抗病毒NK细胞中IRF8的靶点， 分别在目标3中，我们将在抗病毒治疗中测量线粒体健康和代谢。 NK细胞，以研究IRF8介导的效应子和NK细胞存活背后的机制。 在MCMV清除后的收缩期，记忆NK细胞。统称 R01更新的研究不仅将促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，但也 为如何利用NK细胞区室建立新的临床范式 免疫和治疗传染病的策略。