An Immunomics Approach To Explore Drug-Induced Resistance To Schistosomes

探索药物诱导的血吸虫耐药性的免疫组学方法

• 批准号: 8304438
• 负责人: Rodrigo Correa-Oliveira
• 金额: $ 9.24万
• 依托单位: FOUNDATION FOR RESEARCH DEVELOPMENT
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304438
• 关键词: Accounting; Adolescence; Adult; Affect; Aftercare; Age; Antibodies; Antibody Formation; Antibody Repertoire; Antigenic Variation; Antigens; Area; Bioinformatics; Cessation of life; Characteristics; Child; Chronic; Cohort Studies; Data; Drug Kinetics; Epitopes; Evolution; Expressed Sequence Tags; Gender; Genome; Genomics; Helminths; Immune; Immune response; Immune system; Immunity; Individual; Infection; Infectious Agent; Kinetics; Light; Malaria; Measures; Methodology; Modeling; Natural Resistance; Outcome Study; Parasites; Pattern; Peptide Signal Sequences; Pharmaceutical Preparations; Population; Praziquantel; Principal Investigator; Printing; Process; Protein Microchips; Proteins; Proteome; Regimen; Resistance; Risk; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Schistosomiasis; Socioeconomic Status; Surface; Survivors; Systems Biology; Targeted Research; Technology; Testing; Time; Tropical Disease; Tuberculosis; acquired immunity; age related; aged; base; cohort; data exchange; design; disability; early adolescence; epidemiologic data; experience; functional genomics; insight; neglect; research study; sex; transmission process; vaccine development

Schistosoma mansoni infection usually peaks in early adolescence and declines in adulthood, a pattern that has led to the hypothesis that individuals in endemic areas can acquire an age-related resistance to reinfection. The acquisition of this immunity is coincident with the natural death of worms, when they release previously inaccessible surface and subsurface schistosome antigens to the immune system. As the antibody response expands with ongoing worm death, a protective immune response evolves overtime. However, an accelerated version of acquired immunity can be induced "when individuals experience repeated rounds of treatment with the drug praziquantel (PZQ). We hypothesize that both natural (age-related) and Drug-Induced Resistance (DIR) to S. mansoni reinfection have the following characteristics: (1) antibodies are generated to a repertoire of antigens released by PZQ or worm death and not to a single or a few key antigen(s) and (2) there is a gradual expansion of the antibody repertoire as it evolves with worm death either naturally or by PZQ treatment until resistance is achieved. In TMRC Project 1, we utilize a systems biology approach (immunomics) to explore the evolution of DIR in a cohort of children resident in an area of high S. mansoni tranmission. Recent advances in high-order multiplexing technologies, such as proteome microarrays, enable us to determine the immunomic profile of an individual to an annotated predicted proteome of S. mansoni that contains 1000 proteins. This S. mansoni protein microarray will be used to determine the difference in immunomic profiles of individuals who develop DIR to S. mansoni and age, sex, and exposure-matched individuals who are chronically re-infected with S. mansoni. The kinetics of immunomic profiles of DIR individuals will also be determined. Finally, we plan to combine the individual immunomic profiles with data from from Projects 2 and 3 of the TMRC using a "parasite-immune" agent mathemtical model for putative drug-effect on resitance (DIR). A key aspect of our strategy is the capacity to identify large populations of antigens recognized by the antibody responses of a well-characterized cohort who display drug-induced resistance to schistosomiasis (DIRs). RELEVANCE (See instmctions): The outcome of this study will be an "antibody repertoire" associated with the sequential acquisition of DIR. This approach could prove to be a useful strategy for identifying the drug regimens that most efficiently induce immunity as well as provide insight into the kinetics of DIR in areas of S. mansoni transmission. This approach will also shed light on the selection of antigens for vaccine development.

曼森感染血吸虫通常在青春期峰值，成年后的下降，这种模式是 导致了一个假设，即流行地区的个人可以获得与年龄相关的抗药性 重新感染。当蠕虫释放时，对这种免疫力的获取与自然死亡是一致的 以前无法接近免疫系统的表面和地下棘突抗原。作为 抗体反应随着蠕虫的持续死亡而扩展，保护性免疫反应随着时间的流逝而发展。 但是，可以诱发加速的获得的免疫力，“当个人经历重复时 用药物普拉齐特尔（PZQ）进行治疗。我们假设自然（与年龄有关）和 药物诱导的抗性（DIR）对曼氏链球菌的再感染具有以下特征：（1）抗体 由PZQ或WORM死亡释放的抗原曲目产生，而不是单个或几个钥匙 抗原（S）和（2）随着抗体曲目随着蠕虫死亡的发展而逐渐扩展 自然或通过PZQ处理，直到获得阻力为止。在TMRC项目1中，我们使用了一个系统 生物学方法（免疫学）探索在居住在一个地区的一群儿童中DIR的演变 High S. Mansoni Trainersis。高阶多路复用技术的最新进展，例如蛋白质组 微阵列，使我们能够确定个体对带注释的预测的免疫概况 含有1000种蛋白质的Mansoni的蛋白质组。这个曼氏链球菌蛋白微阵列将用于 确定向S. Mansoni和年龄，性别，性别开发DIR的个体免疫概况的差异 与曼森（S.动力学 DIR个体的免疫概况也将得到确定。最后，我们计划结合个人 来自TMRC项目2和3的数据，使用“寄生虫 - 免疫”代理来自项目2和3的数据 假定药物效应的数学模型（DIR）。我们战略的关键方面是能力 通过良好的特征性队列的抗体反应识别大量的抗原种群 谁表现出药物引起的对血吸虫病的抗性（DIRS）。 相关性（请参阅Instmctions）： 这项研究的结果将是与DIR的顺序采集相关的“抗体库”。 这种方法可能被证明是确定最有效的药物方案的有用策略 诱导免疫力，并洞悉曼森（S. Mansoni）传播区域的DIR动力学。这 方法还将阐明用于疫苗开发的抗原的选择。