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，并加深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，因此生命周期内软体动物阶段的中断可能会破坏传播周期。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（但不是唯一）决定因素。具体目标是确定光滑芽胞杆菌-曼氏血吸虫 PR-I 菌株宿主-寄生虫系统中耐药和易感宿主表型的机制，并确定该寄生虫菌株和其他寄生虫菌株导致感染性差异的特性。宿主蜗牛的易感品系和抗性品系中单个寄生虫的独特命运可能是由于宿主的不依赖于氧以及依赖于氧和氮的防御途径的综合作用所致。该研究将使用杀死寄生虫的体外模型，其中将测量和操纵这些途径的酶和产物，获得基因转录本序列，并确定幼稚和受攻击的蜗牛中的转录本水平。将检查与抗性相关的成本基础，并且将使用蛋白质组学和基因组学方法来扩展涉及确定兼容性的基因产物的知识。这些研究将针对宿主和寄生虫进行。将通过比较蛋白质组学和差异基因表达分析来检查不依赖于氧的细胞毒性机制的差异。对合理假设的测试应该有助于更好地理解软体动物宿主的抗性个体成功消除寄生虫的机制，以及寄生虫在面对软体动物先天免疫系统时生存和增殖的方式。所提出的机制可以解释更广泛的菌株和物种中的相容性表型，以及这种寄生中公认的“抗性成本”。

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.