Genetic Modifiers of Immune Evasion by Cytomegalovirus in Glioblastoma

胶质母细胞瘤中巨细胞病毒免疫逃避的基因修饰

基本信息

批准号：
8374071
负责人：
JANARDAN P PANDEY
金额：
$ 22.13万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374071
关键词：
Affect Affinity Affinity Chromatography Alleles Antibodies Antibody Formation Attention Binding CMV glycoprotein B Candidate Disease Gene Cells Chromosomes, Human, Pair 14 Complement Complex Consensus Cytomegalovirus DNA Diagnosis Diagnostic Neoplasm Staging Disease Disease Progression Environment Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Etiology Fc domain Frequencies Genes Genetic Genotype Glioblastoma Glioma Gliomagenesis Herpesviridae IgG1 Immune Immune response Immune system Immunity Immunocompetence Immunoglobulin G Immunologic Monitoring Immunotherapeutic agent Immunotherapy Investigation Laboratories Lead Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Methods Molecular Monitor Neoplastic Processes Pathogenesis Patients Phagocytosis Plasma Population Predisposition Prevalence Property Protein Binding Proteins Risk Role Series Seroprevalences Serum Surface Plasmon Resonance Testing Tumor Promoters Tumor stage Viral Virus antibody-dependent cell cytotoxicity brain cell comparative genome-wide killings novel promoter receptor research study tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Increasing evidence implicates human cytomegalovirus (HCMV) in the etiology of glioblastoma (GBM): HCMV proteins have been implicated as tumor promoters in gliomagenesis; glioma grade-as well as patient survival-directly correlates with the level of HCMV gene products. In this proposal, we seek to understand why this common herpesvirus causes disease in only a subset of those infected: HCMV seroprevalence, 80% vs. the prevalence of GBM, 0.025%. HCMV has evolved highly sophisticated immune evasion strategies. One strategy involves generating two proteins-encoded by genes TRL11/IRL11 and UL119-UL118-that have functional properties of the Fc?R, which may enable the virus to evade host immunosurveillance by evading the effector consequences of antibody binding, such as ADCC. Recent studies from our laboratory show that alleles of a major gene complex of the immune system-GM allotypes encoded by three highly polymorphic IGHG loci on chromosome 14-modulate this viral strategy: The HCMV TRL11/IRL11-encoded Fc?R has significantly higher affinity for IgG1 proteins expressing the GM 3+,1-,2- allotypes than for those expressing the allelic GM 17+,1+,2+ allotypes (p = 0.0005). These observations led us to hypothesize that GM genes are effect modifiers of HCMV-GBM association and the underlying mechanisms include their contribution to anti-HCMV antibody responses and their modulating influence on the viral immune-evasion strategies. The following specific aims will test our hypothesis: 1) Determine if the distribution of GM determinants in GBM patients is different from that in controls. DNA from GBM patients and controls will be genotyped for several GM alleles. Because of their higher affinity to the HCMV-encoded Fc?R, anti-HCMV IgG1 antibodies expressing the GM 3+,1-,2- allotypes would be more likely to have their Fc domains scavenged, thereby reducing their immunological competence to eliminate the virus through ADCC and other Fc-mediated effector mechanisms. Consequently, the frequency of these allotypes would be expected to be higher in patients than in controls; 2) Compare the levels of anti-HCMV antibodies in GBM patients and in controls, and determine if they are associated with particular GM alleles. Antibodies to HCMV glycoprotein B (gB) in the sera/plasma of patients and controls will be quantitated by an ELISA and the levels will be compared between the two groups. We will also determine whether the antibody levels are associated with particular GM alleles; 3) Determine if HCMV-encoded Fc?R proteins bind differentially with genetically disparate Fc (GM) regions of anti-HCMV IgG antibodies in GBM patients. Ectodomains of HCMV-encoded Fc?Rs will be cloned and expressed. We will purify IgG antibodies directed against HCMV gB from the sera of GBM patients. Binding and comparative affinities of IgG molecules of different GM allotypes to the HCMV Fc?Rs will be monitored by surface plasmon resonance. Results from the proposed investigation are likely to open a new avenue of investigation in a malignancy that kills approximately 13000 people every year in the U.S. alone. PUBLIC HEALTH RELEVANCE: Glioblastoma is a highly lethal brain cancer. Cytomegalovirus, a common herpesvirus, has been implicated in the etiology of this malignancy. This project investigates the role of a major gene of the immune system in the etiopathogenesis of cytomegalovirus-spurred glioblastoma. Results from these investigations could help devise novel immunotherapeutic strategies against this cancer.

描述（由申请人提供）：越来越多的证据表明，胶质母细胞瘤（GBM）病因（GBM）中人类巨细胞病毒（HCMV）：HCMV蛋白在神经胶质性中已被视为肿瘤启动子；神经胶质瘤级别以及患者的生存与HCMV基因产物的水平直接相关。在此提案中，我们试图理解为什么这种常见的疱疹病毒仅在感染者中引起疾病：HCMV血清阳性，80％比GBM的患病率，0.025％。 HCMV发展了高度复杂的免疫逃避策略。一种策略涉及产生两个由基因TRL11/IRL11和UL119-UL118的蛋白质编码的蛋白质，该蛋白具有FC？r的功能特性，它们可以通过避免抗体结合的效应子后果来逃避宿主免疫监测，例如ADCC，例如ADCC。 Recent studies from our laboratory show that alleles of a major gene complex of the immune system-GM allotypes encoded by three highly polymorphic IGHG loci on chromosome 14-modulate this viral strategy: The HCMV TRL11/IRL11-encoded Fc?R has significantly higher affinity for IgG1 proteins expressing the GM 3+,1-,2- allotypes than for those expressing the allelic GM 17+，1+，2+同型（P = 0.0005）。这些观察结果导致我们假设GM基因是HCMV-GBM关联的效应修饰符，而潜在的机制包括它们对抗HCMV抗体反应的贡献及其对病毒免疫驱除策略的调节影响。以下具体目的将检验我们的假设：1）确定GBM患者中GM决定因素的分布是否与对照组中的分布不同。 GBM患者和对照组的DNA将用于几个GM等位基因的基因分型。由于它们与HCMV编码的FC？r具有更高的亲和力，因此表达GM 3+，1-，2-同型的抗HCMV IgG1抗体更有可能被清除，从而使其FC域被清除，从而通过ADCC和其他FC介导的效应效应效应效应效应，从而降低其免疫学能力，从而消除其免疫能力。因此，预计患者的这些同种型的频率将高于对照组。 2）比较GBM患者和对照组中抗HCMV抗体的水平，并确定它们是否与特定的GM等位基因相关。患者和对照组的血清/血浆中HCMV糖蛋白B（GB）的抗体将由ELISA进行定量，并且将在两组之间进行比较。我们还将确定抗体水平是否与特定的GM等位基因相关。 3）确定HCMV编码的FC？R蛋白是否与GBM患者的抗HCMV IgG抗体的遗传上不同的FC（GM）区域有不同结合。 HCMV编码的FC？rs的外生分域将被克隆和表达。我们将纯化针对GBM患者血清的HCMV GB的IgG抗体。与HCMV FC？RS不同GM同型IgG分子的结合和比较亲和力将通过表面等离子体共振监测。拟议的调查结果可能会开放新的调查途径，这种恶性肿瘤每年在美国就每年约有13000人丧生。公共卫生相关性：胶质母细胞瘤是一种高度致命的脑癌。巨细胞病毒是一种常见的疱疹病毒，与这种恶性肿瘤的病因有关。该项目研究了免疫系统的主要基因在巨细胞病毒杂化胶质母细胞瘤的疗法发生中的作用。这些研究的结果可以帮助制定针对该癌症的新型免疫治疗策略。