Underlying mechanisms of schistosome/snail compatibility

描述(由申请人提供)：长期目标是打破血吸虫病向人类传播的循环，并扩大对寄生虫在具有免疫能力的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蜗牛光滑生物，从而中断软体动物内生命周期的阶段，从而打破传播周期。我们的假设是，在软体动物血吸虫病的早期阶段，宿主血细胞呼吸爆发的产物和寄生虫的反防御是寄生虫命运的主要(但不是排他性的)决定因素。其具体目的是确定光面血吸虫-曼氏血吸虫PR-I株宿主-寄生虫系统中耐药和敏感宿主表型的机制，并鉴定该株和其他寄生虫株的特性，以解释感染性的差异。在敏感和抗性品系的钉螺中，单个寄生虫的不同命运可能是由于宿主的氧非依赖和氧和氮依赖的防御途径的综合作用。这项研究将使用体外寄生虫杀灭模型，在该模型中，将测量和操纵这些途径的酶和产物，获得基因转录序列，并确定幼稚和受到挑战的蜗牛的转录水平。将研究与抗性相关的成本基础，并将使用蛋白质组学和基因组学方法来扩展与确定配合性有关的基因产品的知识。这些研究将同时针对宿主和寄生虫进行。氧非依赖性细胞毒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验。对合理假设的测试应该能更好地理解软体动物宿主中具有抵抗力的个体成功消除寄生虫的机制，以及寄生虫在对抗软体动物固有免疫系统时生存和繁殖所使用的手段。所提出的机制可能解释了在更广泛的菌株和物种中的亲和性表型，以及在这种寄生中公认的“抗药性代价”。

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.