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：
10669344
负责人：
Joseph Chai-Yuen Sun
金额：
$ 63.03万
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：
2023
资助国家：
美国
起止时间：
2023-01-13 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669344
关键词：
Ablation Activated Natural Killer Cell Adaptive Immune System Antigens Apoptosis Automobile Driving Autophagocytosis B-Lymphocytes Binding Binding Sites Biological Cancer Patient Cell Survival Cell physiology Cells ChIP-seq Chromatin Clinical Clonal Expansion Communicable Diseases Cytomegalovirus Cytomegalovirus Infections DNA Binding DNA Binding Domain Data Development Disease Effector Cell Epigenetic Process Excision Exhibits Family Funding Gene Targeting Genes Genetic Transcription Glycolysis Goals Grant Health Helix-Turn-Helix Motifs Herpesviridae Human IRF4 gene Immune Immunocompromised Host Immunologic Memory Immunoprecipitation In Vitro Individual Inflammatory Innate Immune Response Interferon Type II Invaded Knockout Mice Life Ligation Lymphocyte Lymphoid Mass Spectrum Analysis Measures Mediating Memory Metabolic Metabolic Control Metabolism Mitochondria Modeling Molecular Monkeys Murid herpesvirus 1 Mus NF-kappa B NK Cell Activation Natural Immunity Natural Killer Cells Newborn Infant Pathway interactions Play Predisposition Proliferating Proteomics Regulation Reporter Role Specificity System T-Lymphocyte Testing Therapeutic Transcription Factor AP-1 Transcriptional Regulation Transgenic Mice Transgenic Organisms Transplant Recipients United States National Institutes of Health Viral Virus Virus Diseases Winged Helix Work adaptive immunity aerobic glycolysis comparative conditional knockout cytokine cytotoxic cytotoxicity epigenetic regulation experimental study in vivo innovation member metabolomics mitochondrial autophagy novel novel therapeutics pathogen permissiveness progenitor receptor response trait transcription factor transcriptome sequencing transcriptomics

项目摘要

Project Summary Natural killer (NK) cells are cytotoxic innate lymphocytes that protect the host against viruses. Newborns and immunocompromised individuals lacking NK cells and are extremely susceptible to viral infection, including herpesviruses such as human cytomegalovirus (HCMV). HCMV can be accurately modeled using mouse cytomegalovirus (MCMV) infection in mice, which represents a robust system for investigating antiviral NK cell responses. From the previous R01 funding period, my lab has discovered new cellular and molecular mechanisms underlying NK cell responses against MCMV. This current R01 renewal seeks to understand the transcriptomic, epigenetic, and metabolic control of the antiviral NK cell response, with studies centering around a novel role for the transcription factor IRF4. In exciting preliminary data, we find IRF4 is rapidly induced in NK cells during MCMV infection and plays a critical role in their effector response. For the proposed experiments, we have generated new transgenic mice with conditional Irf4 ablation. In Aim 1, we will determine how IRF4 is transcriptionally and epigenetically regulated in activated NK cells, and test how IRF4-deficiency impacts the function of NK cells against MCMV infection. Aim 2 will identify novel gene targets and binding partners of IRF4 in NK cells by integrating transcriptomic, epigenetic, and proteomic approaches. In Aim 3, we will investigate whether IRF4 drives antiviral NK cell responses by controlling overall metabolism and mitochondrial health. Altogether, the studies in this R01 renewal will advance our understanding of the molecular basis by which these powerful effector cells can mediate protection against pathogen invasion, and establish innovative clinical paradigms for how NK cells may be harnessed for therapeutic strategies against infectious disease.

项目摘要天然杀伤（NK）细胞是可保护宿主免受病毒的细胞毒性先天淋巴细胞。新生儿和没有NK细胞的免疫功能低下的个体，并且非常容易受到病毒感染的影响，包括疱疹病毒，例如人类巨细胞病毒（HCMV）。可以使用鼠标精确建模HCMV 小鼠中的巨细胞病毒（MCMV）感染，它代表了研究抗病毒NK细胞的强大系统回答。从上一个R01资金期开始，我的实验室发现了新的细胞和分子针对MCMV的NK细胞反应的基础机制。当前的R01更新试图了解抗病毒NK细胞反应的转录组，表观遗传和代谢控制，研究围绕转录因子IRF4的新作用。在令人兴奋的初步数据中，我们发现IRF4在NK中迅速诱导 MCMV感染过程中的细胞在其效应子反应中起关键作用。对于提出的实验，我们已经生成了有条件的IRF4消融的新的转基因小鼠。在AIM 1中，我们将确定IRF4的方式在活化的NK细胞中对转录和表观遗传调节，并测试IRF4缺乏效率如何影响 NK细胞对MCMV感染的功能。 AIM 2将确定IRF4的新基因靶标和结合伴侣在NK细胞中，通过整合转录组，表观遗传学和蛋白质组学方法。在AIM 3中，我们将调查 IRF4是否通过控制总体代谢和线粒体健康来驱动抗病毒NK细胞反应。总之，此R01更新中的研究将提高我们对这些分子基础的理解强大的效应细胞可以介导防止病原体侵袭的保护，并建立创新的临床如何利用NK细胞的范例来针对传染病进行治疗策略。