Determinants of resistance in human schistosomiasis

曼氏血吸虫感染是非洲、中东和南部大部分地区的主要健康问题。 美国参考最近的数据表明，根据再感染的时间，职业暴露于S。曼氏 耐药，在多次治疗/再感染后产生耐药性，或保持易感。这项建议 将检验这一假设，即这些特征良好的肯尼亚人的耐药性与特异性免疫相关， 反应和遗传概况，决定了伴随抗性的动态免疫变化 在这些成年人和学龄儿童中获得，看看免疫变化是否可以预测抵抗力。基于 初步数据、治疗/再感染研究和动物模型，提出耐药性与 Th 1和Th 2免疫谱，这取决于所研究的溶酶体抗原特异性应答。 这一假设将在特征明确的耐药和易感成人中进行检验， 由于多次治疗/再感染而产生耐药性。此外，抗原特异性免疫概况 儿童（通常容易再次感染）将在他们对多种治疗有反应时被确定。的 具体目的是：1）确定抗原特异性细胞因子和抗体同种型应答（免疫应答）。 概况），涉及的阻力或易感性的人职业暴露于S。曼索尼比 流式细胞术、mRNA RT-PCR和基因激活微阵列分析、细胞因子体外培养 生产和增殖，以及抗体ELISA分析。2)确定免疫特征的进展 在对S. mansoni在前瞻性随访队列中。第三章 确定成年人免疫谱的进行性变化是否对S。 在高度流行地区多次治疗的儿童中也纵向发生曼氏病。4)测试 遗传多态性的关系可能与对S.曼氏 在特征明确的抗性或易感性成虫中。这些具体目标的实现将有助于建立 对多次治疗/再感染后发生的病原体感染的抗性基础;提供两者 对未来疫苗开发所需的耐药性/敏感性的机制性见解和相关性 对抗这种使人衰弱的疾病;并确定是否有多个大规模治疗计划来控制发病率 通过诱导对S. mansoni

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/reinfections, 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/reinfections. 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 microarray 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.