Underlying mechanisms of schistosome/snail compatibility

描述（由申请方提供）：长期目标是打破血吸虫病传播给人类的循环，并扩展对寄生虫在免疫活性宿主中生存策略的理解。这一点很重要，因为人类血吸虫病的发生需要成功感染中间宿主光滑双脐螺，因此，生命周期的软体动物内阶段的中断可能会打破传播周期。我们的假设是，在软体动物血吸虫病的早期阶段，宿主血细胞的呼吸爆发和寄生虫的反防御的产品是寄生虫的命运的主要（但不是唯一的）决定因素。具体目标是确定负责B中抗性和敏感宿主表型的机制。光滑-曼氏血吸虫PR-I株宿主-寄生虫系统，并鉴定该寄生虫株和其他寄生虫株的导致感染性差异的特性。个体寄生虫在宿主蜗牛的敏感和抗性品系中的独特命运可能是由于宿主的氧非依赖性和氧和氮依赖性防御途径的综合作用。该研究将使用寄生虫杀死的体外模型，其中这些途径的酶和产物将被测量和操纵，基因转录序列将被获得，转录水平将在幼稚和挑战蜗牛中确定。将检查与抗性相关的成本的基础，并将使用蛋白质组学和基因组学方法来扩展参与确定相容性的基因产物的知识。这些研究将在宿主和寄生虫中进行。氧非依赖性细胞毒性机制的差异将通过比较蛋白质组学和差异基因表达分析来检查。合理的假设的测试，应导致更好地理解的机制，导致成功消除寄生虫的抗性个体的软体动物主机，和寄生虫的生存和增殖，同时面对先天免疫系统的软体动物所使用的手段。建议的机制可能占兼容性表型在更广泛的菌株和物种，并为公认的“成本的阻力”在这种寄生。

DESCRIPTION (provided by the applicant): The long-term objectives are to break the cycle of schistosomiasis transmission to humans, and to extend understanding of parasite strategies for survival in immunocompetent hosts. This is important because the occurrence of human schistosomiasis requires successful infection of the intermediate host snail Biomphalaria glabrata, so that interruption of the intra-molluscan stages of the life cycle could break the transmission cycle. Our hypothesis is that, in the early stages of molluscan schistosomiasis, products of the host hemocytes' respiratory burst and counter-defenses of the parasite are the major (but not exclusive) determinants of the parasite's fate. Specific aims are to determine the mechanisms responsible for the resistant and susceptible host phenotypes in the B. glabrata-Schistosoma mansoni PR-I strain host-parasite system, and to identify properties of this and other strains of the parasite that account for differences in infectivity. The distinctive fates of individual parasites in susceptible and resistant strains of host snail may be due to the combined effects of oxygen-independent and of oxygen- and nitrogen-dependent defense pathways of the host. The research will use in vitro models of parasite killing in which enzymes and products of these pathways will be measured and manipulated, gene transcript sequences will be obtained, and transcript levels will be determined in naive and challenged snails. The basis of a cost associated with resistance will be examined, and both proteomic and genomic approaches will be used to extend knowledge of gene products involved in determining compatibility. These studies will be done with both hosts and parasites. Differences in oxygen-independent cytotoxic mechanisms will be examined by both comparative proteomics and differential gene expression analyses. Tests of plausible hypotheses should lead to a better understanding of the mechanisms that lead to successful elimination of the parasite by resistant individuals of the molluscan host, and the means used by parasites to survive and proliferate while confronting the innate immune system of the mollusk. The suggested mechanisms may account for compatibility phenotypes in a broader range of strains and species, and for the recognized 'cost of resistance' in this parasitism.