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。最近的数据显示，根据再次感染的时间，职业暴露于曼氏葡萄球菌的成年人 耐药，在多次治疗/再感染时产生抗药性，或仍易受影响。这项建议 将检验这样一种假设，即这些特征良好的肯尼亚人的抵抗力与特定的免疫相关 反应和遗传特征决定了伴随耐药性的动态免疫变化 这些成年人和学龄儿童的获得性，并看看免疫变化是否可以预测耐药性。基于 初步数据、治疗/再感染研究和动物模型的耐药性被认为与 Th1和Th2免疫模式，取决于正在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抗性和易感成年人身上以及在那些活跃的成年人身上进行测试。 由于多种治疗/再感染而产生耐药性。此外，该病毒的抗原特异性免疫图谱 儿童(通常容易再次感染)将被确定为对多种治疗有反应。这个 具体目标是：1)确定抗原特异性细胞因子和抗体同型反应(免疫 与职业接触曼氏葡萄球菌的人的抵抗力或敏感性有关 细胞因子体外培养的流式细胞术、基因转录-聚合酶链式反应和基因激活微阵列分析 生产和增殖，并进行抗体酶联免疫吸附分析。2)确定免疫模式的进展 在对曼氏葡萄球菌的实际发展过程中的变化在前瞻性队列中进行了跟踪。3) 确定成年后观察到的免疫特征的渐进性变化是否会对S。 在高度流行的地区，经多次治疗的儿童也会纵向感染曼森氏肺炎。4)测试 可能与曼氏葡萄球菌耐药性或敏感性相关的基因多态关系 在具有良好特性的抗性或敏感成虫身上。完成这些具体目标将有助于建立 在多次治疗/再感染时对血吸虫感染产生抵抗力的基础；提供两者 对未来疫苗开发所需的耐药性/敏感性的机械性洞察及其相关性 对抗这种令人衰弱的疾病；并确定是否有多种大规模治疗计划来控制发病率 通过诱导对曼氏沙门氏菌再次感染产生一定程度的抵抗力，提供额外的好处。

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.