Modeling Drug Induced Resistance in S. mansoni Endemic Areas

曼氏沙门氏菌流行地区药物诱导耐药性建模

• 批准号: 8264247
• 负责人: Rodrigo Correa-Oliveira
• 金额: $ 26.98万
• 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/8264247
• 关键词: Accounting; Adult; Affect; Aftercare; Age; Antibodies; Antibody Formation; Antibody Repertoire; Antigens; Area; Behavioral; Biological; Biological Markers; Brazil; Cessation of life; Characteristics; Child; Chronic; Cohort Studies; Communities; Complement; Data; Dependence; Development; Doctor of Philosophy; Drug Kinetics; Drug resistance; Ecology; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Evolution; Exposure to; Genetic Variation; Genomics; Goals; Helminths; Household; Immune; Immune response; Immune system; Immunity; Individual; Infection; Intervention; Kinetics; Light; Methodology; Modeling; Molecular; Monitor; Morbidity - disease rate; Outcome Study; Parasites; Pattern; Pharmaceutical Preparations; Population; Population Dynamics; Population Sizes; Praziquantel; Prevalence; Preventive; Principal Investigator; Process; Protein Microchips; Proteins; Proteome; Recording of previous events; Regimen; Relative (related person); Research; Resistance; Resistance development; Resistance to infection; Risk; Role; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Schistosome Parasite; Schistosomiasis; Simulate; Site; Source; Structure; Surface; Systems Biology; Targeted Research; Technology; Time; acquired immunity; age related; aged; base; cohort; design; disability; disease transmission; early adolescence; experience; improved; innovation; insight; mathematical model; novel; programs; response; sex; social; socioeconomics; tool; transmission process; vaccine development; virtual

DESCRIPTION (provided by applicant): This TMRC presents an innovative approach to understand host-parasite dynamics of Schistosoma mansoni infection in an endemic population in Brazil. The overall goal of this TMRC is to utilize new information on resistance-related host immune response, combined with fine-scale data on environmental exposures, in order to develop an informative, detailed model of transmission in endemic areas that can be used to efficiently allocate monitoring and preventive control efforts for schistosomiasis. The research will provide detailed study of immune responses among individuals who develop resistance to reinfection after treatment - termed here. Drug Induced Resistance (DIR). For the first time, by evaluating immune responses using a novel broad-based immunomics approach, we will be able to identify the constellation of parasite proteins recognized by DIR individuals. Such analysis will identify important biomarkers of resistance that can be used to time the onset of resistance to infection according to the dynamics of individual re-exposure. Besides the impact on the immune response, intensive treatment also has significant effect on the parasite population. We will apply molecular tools that will complement traditional epidemiology to provide a better understanding of disease transmission, the impact of praziquantel drug treatment over time and the adaptability of the schistosome parasite. We will use new molecular and statistical tools to assess the adaptive potential and identify focal points of transmission of the S. mansoni. The role of eco-social and environmental factors will be evaluated using an agent-based mathematical model. Within-host models of schistosomiasis infection that would account for the effects of environment, exposure to the infection, possible effect of drug treatment and other (helminth) coinfections will also be developed in the context of this integrated approach. Taken together, the immunomics, understanding of the parasite population diversity and the eco-socio-economic, behavioral, and spatial components of exposure, this project will ultimately provide an advanced model of transmission that can be used for development of optimized control programs for schistosomiasis in Brazil and other endemic areas. RELEVANCE: The results will provide key data that are needed to model schistosome transmission and drug selection and result in the design of more effective control interventions. Project 1: An Immunomics Approach to Explore Drug-Induced Resistance to Schistosomes Project Leader: Rodrigo Correa-Oliveira, PhD (Description as provided by applicant): 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 transmission. 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 Projects 2 and 3 of the TMRC using a "parasite-immune" agent mathematical model for putative drug-effect on resistance (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: 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.

描述（由申请人提供）：该TMRC提出了一种创新的方法，可以理解巴西一个地方性人群中曼氏菌感染的宿主 - 寄生虫动力学。该TMRC的总体目标是利用有关阻力相关的宿主免疫反应的新信息，结合了有关环境暴露的精细数据，以开发一种可用于有效分配SCISTOSOMIASIS的传播区域的信息，可用于有效地分配监测和预防性控制工作的地方性传播模型。这项研究将对在此处称为治疗后产生抵抗力再感染的个体中的免疫反应进行详细研究。药物诱导的抗性（DIR）。首次使用一种新型的基于广泛的免疫学方法评估免疫反应，我们将能够识别出DIR个体认可的寄生虫蛋白的星座。这种分析将确定抗药性的重要生物标志物，可用于根据个人重新暴露的动力学计算对感染的抗性发作。除了对免疫反应的影响外，强化治疗对寄生虫种群也有重大影响。我们将应用分子工具，以补充传统的流行病学，以更好地了解疾病传播，随着时间的推移随着时间的推移的影响以及血吸虫寄生虫的适应性的影响。我们将使用新的分子和统计工具来评估自适应潜力并确定传播的焦点 S. Mansoni。生态社会和环境因素的作用将使用基于代理的数学模型进行评估。在这种综合方法的背景下，还将开发出宿主性血吸虫病感染的内主模型，该模型将解释环境的影响，暴露于感染的影响，药物治疗和其他（Helminth）共感染的影响。综上所述，免疫学，对寄生虫种群多样性的理解以及暴露的生态社会经济，行为和空间组成部分，该项目最终将提供一种先进的传播模型，可用于开发巴西和其他地方性领域的优化控制程序。 相关性：结果将提供所需的关键数据，以建模实体体传播和药物选择，并导致设计更有效的控制干预措施。 项目1：一种免疫学方法，探索药物诱导的对血吸虫的抗性 项目负责人：Rodrigo Correa-Oliveira，博士 （申请人提供的描述）：曼氏菌感染通常在青春期峰值峰值，成年后的下降，这种模式导致了一个假设，即流行地区的个体可以获得与年龄相关的抗抑制性。这种免疫力的获取与蠕虫的自然死亡是一致的，当时它们以前无法访问的表面和地下黑螺杆菌抗原释放到免疫系统中。随着抗体反应随着蠕虫的持续死亡的扩展，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“当个人与药物praziquantel（PZQ）进行重复治疗时。我们假设自然（与年龄相关）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）PZQ或WORM死亡释放的抗原的抗体生成抗体，而不是单个或几个关键的抗原（S），并且（2）逐渐扩大了抗体库的扩张，因为它可以自然地对其进行了抗体的影响，或者是pzq a iT iT iT iT iT iT iT iT iT iT iT iT iT iS PZQ进行了pzq con iT i pzq con的持续性。在TMRC项目1中，我们利用系统生物学方法（免疫学）来探索DIR在居住在高级S. Mansoni传播领域的儿童队列中的演变。高阶多路复用技术（例如蛋白质组微阵列）的最新进展使我们能够确定个体对含有1000种蛋白质的曼氏链球菌的预测蛋白质组的免疫谱。这种曼氏链球菌蛋白微阵列将用于确定向曼森（S. Mansoni）开发DIR以及年龄，性别和暴露匹配的个体的个人的免疫特征的差异，这些个体长期重新感染了S. Mansoni。还将确定DIR个体免疫特征的动力学。最后，我们计划使用“寄生虫 - 免疫”试剂数学模型将单个免疫概况与来自TMRC项目2和3的数据结合起来，以实现推定的抗药性药物效应（DIR）。我们策略的一个关键方面是能够通过表现出良好的抗体反应来识别大量抗原种群，该抗体反应表现出对药物诱导的对棘疾病的抗性（DIRS）。 相关性：这项研究的结果将是与DIR的顺序获取相关的“抗体库”。这种方法可能被证明是确定最有效诱导免疫力的药物方案的有用策略，并可以深入了解曼氏链球菌传播区域中DIR的动力学。这种方法还将阐明用于疫苗开发的抗原的选择。