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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：
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.

项目总结