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S。曼氏菌具有耐药性，在多次治疗/再感染后产生耐药性，或保持易感。该提案将测试这一假设，即这些特征良好的肯尼亚人的耐药性与特定的免疫反应和遗传特征相关，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。基于初步数据、治疗/再感染研究和动物模型，提出抗性与Thl和Th 2免疫概况两者相关，这取决于所研究的抗体抗原特异性应答。将在充分表征的耐药和易感成人以及因多次治疗/再感染而积极发展耐药的成人中检验这一假设。此外，将确定儿童（通常易受再感染）的抗原特异性免疫特征，因为他们对多种治疗有反应。具体目标是：1）确定与职业暴露于S的人的抗性或易感性相关的抗原特异性细胞因子和抗体同种型反应（免疫谱）。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分析来检测曼氏曼氏菌。2)确定在对S的实际耐药性发展过程中免疫谱变化的进展。mansoni在前瞻性随访队列中。3)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)检测可能与对沙门氏菌的抗性或易感性相关的遗传多态性的关系。曼森氏菌在充分表征的抗性或易感性成虫中。完成这些特定目标将：帮助建立对多重治疗/再感染后发生的沙门氏菌感染的抗性基础;提供对未来针对这种衰弱性疾病的疫苗开发所需的抗性/敏感性的机制见解和相关性;并确定通过诱导对沙门氏菌再感染的抗性水平来控制发病率的多重大规模治疗计划是否提供额外的益处。mansoni

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.