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.

项目总结 1爱泼斯坦-巴尔病毒(EBV)感染了大约95%的人，大多数人都有无症状的潜伏 2感染。然而，在某些情况下，EBV可导致免疫病理和恶性疾病，导致1%的 3例全球癌症死亡病例。免疫系统在决定无症状和非典型肺炎之间的平衡方面是至关重要的 4病原性感染。自然杀伤(NK)细胞发挥重要作用：NK细胞识别和杀伤EBV感染 5细胞，NK细胞缺乏导致严重的EBV病。自然杀伤细胞功能是由生殖系编码的 6 NK细胞受体，与感染细胞上表达的配体结合。在这些受体中有杀伤细胞 7免疫球蛋白样受体(KIR)，识别人类白细胞抗原(HL A)为配体。两个KIR 8和人类白细胞抗原是高度多态的，它们的连接是同种异型特有的，因此个体具有独特的 9决定其NK细胞对感染反应的人类白细胞抗原和KIR同种异型库。此外，具体的 人类白细胞抗原提呈的10肽可以改变KIR的连接，其中包括3个已知能改变KIR与人类白细胞抗原结合的EBV多肽。 11有趣的是，KIR、人类白细胞抗原和EB病毒的基因变异分别与EBV病有关，我有 观察到12个EBV多态，这些多态可能改变KIR和人类白细胞抗原之间的多肽结合。 13虽然这些遗传关联表明，人类白细胞抗原、KIR和EBV基因决定了不同功能的NK细胞 EBV致病过程中的14个反应，KIR/HLA基因变异对控制EBV感染的影响 15到疾病的发病，以及宿主和病毒遗传变异之间的相互作用，仍然没有明确的特征。此外， 16 KIR介导的抗EBV免疫背后的免疫学机制尚未从功能上定义。 17拟议的研究将检验KIR和人类白细胞抗原多肽之间的同种异型特异性连接的假设 18个复合体决定了个体和EBV毒株之间的NK细胞反应，导致了基因依赖 19 EB病毒感染的免疫控制。目标1将确定KIR、人类白细胞抗原和EB病毒的基因型别 20个与循环EBV载量有关的样本，使用来自20个不同人群的样本。这些基因 21个关联将与KIR-HLA功能数据整合，如连接亲和力和信号强度，以 22认识NK细胞教育和抗原识别在控制EBV感染中的作用。目标2将是补充 23通过功能性测试KIR和HLA同种异型对的指导能力来确定遗传关联 24例NK细胞对EBV感染细胞具有杀伤功能。NK细胞识别的KIR和HLA同种异型 将鉴定出25%的EBV感染细胞，以及启用或破坏NK的EBV多肽和多态 26通过KIR和人类白细胞抗原杀伤细胞。综上所述，这些目标将决定人类白细胞抗原和KIR基因多态性在 27 NK细胞介导的EBV感染控制，阐明了驱动EBV感染的免疫学机制 28例EB病毒病与人类白细胞抗原、KIR和EB病毒基因型别相关。拟议的研究和 29方法论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过渡到终身教职所必需的背景，研究DNA病毒免疫的遗传学基础。