Determinants of resistance in human schistosomiasis

描述（由申请人提供）：曼氏血吸虫感染是非洲、中东和南美大部分地区的主要健康问题。最近的数据显示，根据再感染时间，职业暴露于曼氏链球菌的成年人具有耐药性，在多次治疗/再次感染时产生耐药性，或仍然易感。这一提议将检验这样一种假设，即这些特征明确的肯尼亚人的耐药性与特定的免疫反应和遗传谱相关，确定这些成年人和学龄儿童获得耐药性时伴随的动态免疫变化，并观察免疫变化是否可以预测耐药性。根据初步数据、治疗/再感染研究和动物模型，耐药性可能与Thl和Th2免疫谱相关，这取决于所研究的血吸虫抗原特异性反应。这一假设将在具有良好特征的耐药和易感成年人以及因多次治疗/再次感染而积极产生耐药的成年人中进行检验。此外，儿童（通常容易再次感染）的抗原特异性免疫谱将在他们对多种治疗有反应时确定。具体目的是：1)通过流式细胞术、mRNA RT-PCR和基因激活微阵列分析、细胞因子产生和增殖的体外培养以及抗体ELISA分析，确定抗原特异性细胞因子和抗体同型反应（免疫谱）与职业暴露于曼氏梭菌的人的耐药性或易感性相关。2)在前瞻性随访队列中确定对曼氏链球菌耐药实际发展过程中免疫谱变化的进展。3)确定在成人对曼氏链球菌产生耐药性时观察到的免疫谱进行性变化是否也会在高度流行地区接受多次治疗的儿童中纵向发生。4)在具有良好特征的耐药或易感成人中，检测可能与曼氏梭菌耐药或易感相关的遗传多态性的关系。完成这些具体目标将：有助于建立抵抗多次治疗/再感染时发生的血吸虫感染的基础；为未来开发针对这种使人衰弱的疾病的疫苗提供所需的耐药性/易感性的机制见解和相关因素；并确定控制发病率的多个大规模治疗方案是否通过诱导对曼氏梭菌再感染的一定程度的抵抗而提供额外的益处。

DESCRIPTION (provided by the applicant): Infection with Schistosoma mansoni is a major health problem in much of Africa, the Middle East, and South America. Recent data show that based on time to reinfection, adults occupationally exposed to S. mansoni are resistant, develop resistance upon multiple treatments/re-infections, or remain susceptible. This proposal will test the hypothesis that resistance in these well-characterized Kenyans correlates with specific immune responses and genetic profiles, determine the dynamic immune changes accompanying resistance acquisition in these adults and school children, and see if immune changes can predict resistance. Based on preliminary data, treatment/reinfection studies, and animal models, resistance is proposed to correlate with both Thl and Th2 immune profiles, depending on the schistosome antigen-specific responses being studied. This hypothesis will be tested in well-characterized resistant and susceptible adults, and in those actively developing resistance due to multiple treatments/re-infections. Also, the antigen-specific immune profiles of children (usually susceptible to reinfection) will be determined as they respond to multiple treatments. The Specific Aims are: 1) Determine the antigen-specific cytokine and antibody isotype responses (immune profiles) that relate to the resistance or susceptibility of persons occupationally exposed to S. mansoni by flow cytometry, mRNA RT-PCR and gene activation micro-array analyses, in vitro culture for cytokine production and proliferation, and antibody ELISA analyses. 2) Determine the progression of immune profile changes during the actual development of resistance to S. mansoni in a prospectively followed cohort. 3) Determine if the progressive changes in immune profiles that are observed as adults become resistant to S. mansoni also occur longitudinally in multiply treated children in a highly endemic area. 4) Test the relationships of genetic polymorphisms likely to be associated with resistance or susceptibility to S. mansoni in well-characterized resistant or susceptible adults. Completion of these Specific Aims will: help establish the basis of resistance to schistosome infection that occurs upon multiple treatment/reinfection; provide both mechanistic insights into and correlates of resistance/susceptibility needed for future vaccine development against this debilitating disease; and determine if multiple mass treatment programs to control morbidity provide an added benefit by inducing a level of resistance to reinfection by S. mansoni.