Variable natural killer cell responses in the control of Epstein-Barr virus infection

控制 Epstein-Barr 病毒感染的可变自然杀伤细胞反应

• 批准号: 10462904
• 负责人: William Hunt Palmer
• 金额: $ 2.62万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2022-10-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462904
• 关键词: Affinity; Alleles; Antigens; Automobile Driving; Avidity; B-Lymphocytes; Binding; Biological Assay; Cell Line; Cell physiology; Cells; Cellular biology; Cessation of life; Complement; Complex; DNA; DNA Viruses; DNA sequencing; Data; Disease; Education; Effector Cell; Epstein-Barr Virus Infections; Epstein-Barr pathogenesis; Equilibrium; Etiology; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genetic Variation; Genetic study; Genotype; Goals; HLA Antigens; Histocompatibility Antigens Class I; Hodgkin Disease; Human; Human Genetics; Human Herpesvirus 4; Immune; Immune response; Immune system; Immunity; Immunoglobulins; Immunologics; Immunology; In Vitro; Incubated; Individual; Infection; Infection Control; Infectious Mononucleosis; Killer Cells; Knock-out; Lead; Ligands; Ligation; Lytic; Lytic Phase; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Meta-Analysis; Methodology; Modeling; Nasopharynx Carcinoma; Natural Killer Cells; Onset of illness; Pathogenicity; Pathology; Peptides; Play; Population Heterogeneity; Positioning Attribute; Proxy; Receptor Cell; Reporting; Research; Risk; Role; Sampling; Signal Transduction; Testing; Training; Variant; Viral; Viral load measurement; Virus Diseases; antigen binding; antiviral immunity; arm; career; cell killing; disorder risk; experimental study; genetic architecture; genetic association; genetic variant; insight; latent infection; lytic replication; peripheral blood; preference; receptor; reconstitution; response; tenure track; tool; viral DNA; virus genetics

Project summary 1 Epstein-Barr virus (EBV) infects approximately 95% of individuals, with most having an asymptomatic, latent 2 infection. However, EBV can drive immunopathological and malignant diseases in some, resulting in >1% of 3 global cancer deaths. The immune system is critical in determining the balance between asymptomatic and 4 pathogenic infection. Natural Killer (NK) cells play an important role: NK cells recognize and kill EBV-infected 5 cells, and NK cell deficiencies lead to severe EBV disease. NK cell functions are modulated by germline-encoded 6 NK cell receptors, which engage ligands expressed on infected cells. Among these receptors are the Killer cell 7 immunoglobulin-like receptors (KIR), which recognize Human Leukocyte Antigen (HLA) as ligands. Both KIR 8 and HLA are extremely polymorphic, and their ligation is allotype-specific, such that individuals have a unique 9 repertoire of HLA and KIR allotypes that determines their NK cell response to infection. Further, the specific 10 peptide presented by HLA can alter KIR ligation, including three EBV peptides known to alter KIR-HLA binding. 11 Intriguingly, genetic variants in KIR, HLA, and EBV are individually associated with EBV disease, and I have 12 observed EBV polymorphism in positions expected to alter peptide-specific binding between KIR and HLA. 13 While these genetic associations suggest HLA, KIR, and EBV genotypes determine functionally distinct NK cell 14 responses during EBV pathogenesis, the impact of KIR/HLA genetic variation in controlling EBV infection prior 15 to disease onset, and the interactions between host and viral genetic variation, remain uncharacterized. Further, 16 the immunological mechanisms behind KIR-mediated antiviral immunity to EBV are not functionally defined. 17 The proposed research will test the hypothesis that allotype-specific ligation between KIR and HLA-peptide 18 complexes determine NK cell responses across individuals and EBV strains, resulting in genotype-dependent 19 immune control of EBV infection. Aim 1 will identify the KIR, HLA, and EBV genotypes that are individually or 20 jointly associated with circulating EBV load, using samples from 20 diverse populations. These genetic 21 associations will be integrated with KIR-HLA functional data, such as ligation avidity and signaling strength, to 22 discern the role of NK cell education and antigen recognition in controlling EBV infection. Aim 2 will complement 23 the identified genetic associations by functionally testing the ability of pairs of KIR and HLA allotypes to direct 24 NK cell cytolytic functions towards EBV-infected cells. KIR and HLA allotypes that underlie NK cell recognition 25 of EBV-infected cells will be identified, as will the EBV peptides and polymorphisms that enable or disrupt NK 26 cell killing through KIR and HLA. Together, these aims will determine the role of HLA and KIR polymorphism in 27 the NK cell-mediated control of EBV infection, providing clarity on the immunological mechanisms driving 28 established associations between EBV disease and HLA, KIR, and EBV genotypes. The proposed research and 29 methodologies will also facilitate my training in human immunology and genetics research, providing the 30 background necessary to transition into a tenure-track role studying the genetics underlying DNA virus immunity.

项目摘要 1爱泼斯坦 - 巴尔病毒（EBV）感染了约95％的个体，大多数有无症状的潜在 2感染。但是，EBV可以在某些人中驱动免疫病理和恶性疾病，导致> 1％ 3个全球癌症死亡。免疫系统对于确定无症状和 4致病感染。天然杀手（NK）细胞起着重要作用：NK细胞识别并杀死EBV感染的 5个细胞和NK细胞缺陷导致严重的EBV疾病。 NK细胞功能由种系编码调节 6 NK细胞受体，它们接合在感染细胞上表达的配体。这些受体中有杀伤细胞 7个免疫球蛋白样受体（KIR），它们将人白细胞抗原（HLA）识别为配体。两个Kir 8和HLA极其多态，其连接是特定于同种型的，因此个体具有独特的 9 HLA和KIR同型决定其NK细胞对感染的反应。此外，具体 HLA提出的10肽可以改变KIR连接，包括三种已知可以改变Kir-HLA结合的EBV肽。 11有趣的是，KIR，HLA和EBV中的遗传变异与EBV疾病单独相关，我有 12观察到EBV多态性在预期改变KIR和HLA之间的肽特异性结合的位置。 13尽管这些遗传关联表明HLA，KIR和EBV基因型决定了功能上不同的NK细胞 14在EBV发病机理期间的反应，KIR/HLA遗传变异在控制EBV感染中的影响 15疾病发作以及宿主与病毒遗传变异之间的相互作用仍然没有特征。更远， 16 KIR介导的对EBV的抗病毒免疫背后的免疫机制未定义。 17拟议的研究将检验以下假设：KIR和HLA肽之间的异型特异性连接 18个复合物决定了个体和EBV菌株之间的NK细胞反应，从而导致基因型依赖性 19对EBV感染的免疫控制。 AIM 1将识别单独或单独的KIR，HLA和EBV基因型 20种与循环EBV负载相关的，使用来自20种不同种群的样品。这些遗传 21个关联将与KIR-HLA功能数据（例如连接亲和信号强度）集成到 22辨别NK细胞教育和抗原识别在控制EBV感染中的作用。 AIM 2将补充 23鉴定的遗传关联是通过功能测试KIR和HLA异型对导向的能力 24 NK细胞细胞溶解功能对EBV感染的细胞。基于NK细胞识别的KIR和HLA同型 将确定25个EBV感染的细胞，EBV肽和多态性也会被识别 26细胞通过KIR和HLA杀死。这些目标共同决定了HLA和KIR多态性在 27 NK细胞介导的EBV感染的控制，提供了驱动免疫机制的清晰度 28 EBV病与HLA，KIR和EBV基因型之间建立了关联。拟议的研究和 29方法还将促进我在人类免疫学和遗传学研究方面的培训，提供 30过渡到研究DNA病毒免疫遗传学的终身轨道作用所必需的背景。