Determinants of resistance in human schistosomiasis

描述(由申请人提供)：曼氏血吸虫感染是非洲、中东和南美洲大部分地区的主要健康问题。最近的数据表明，根据再感染的时间，职业暴露于曼氏葡萄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，或者仍然敏感。这项提议将检验这样的假设，即这些特征良好的肯尼亚人的抵抗力与特定的免疫反应和基因特征相关，确定这些成年人和学龄儿童获得抵抗力的动态免疫变化，并看看免疫变化是否可以预测抵抗力。根据初步数据、治疗/再感染研究和动物模型，根据正在研究的血吸虫抗原特异性反应，耐药性被认为与Th1和Th2免疫特征有关。这一假设将在具有良好特征的抗药性和易感成年人中进行测试，以及在那些由于多种治疗/再次感染而积极发展抗药性的成年人中进行测试。此外，还将确定儿童(通常容易再次感染)的抗原特异性免疫图谱，因为他们对多种治疗有反应。其具体目的是：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，确定与曼氏葡萄球菌耐药或易感性有关的抗原特异性细胞因子和抗体同型反应(免疫图谱)。2)在前瞻性跟踪队列中，确定对曼氏葡萄球菌的实际抗药性发展过程中免疫谱变化的进展。3)确定在成人对曼氏葡萄球菌产生抗药性时观察到的免疫图谱的进行性变化是否也纵向地发生在高度流行地区多次治疗的儿童中。4)在特征明确的抗性或敏感成人中，测试可能与曼氏血吸虫抗性或敏感性相关的遗传多态的关系。这些具体目标的完成将有助于：帮助建立在多次治疗/再感染时对血吸虫感染产生抗药性的基础；提供对未来针对这种衰弱疾病的疫苗开发所需的抗药性/敏感性的机械性见解和相关性；以及确定通过诱导对曼氏血吸虫再感染的抗药性水平来控制发病率的多种大规模治疗计划是否提供额外的好处。

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.