Transport pathways of host-derived iron in schistosomes parasites

该项目将确定人体寄生血吸虫(血吸虫)体表表达的代谢铁受体的多样性和生物学作用。在许多热带国家，血吸虫是一个主要的健康问题，并造成严重的人类发病率和生产力损失。成虫以人类血液为食，从血液中提取氨基酸，以生产每天释放到人类血液中的数百个卵。寄生在人体器官中的寄生虫卵引起的强烈细胞反应是导致人类慢性疾病的主要原因。我们发现了血吸虫体内两种耐人寻味的铁代谢现象。首先，血吸虫比许多其他生物对铁的依赖程度更高，将多余的铁储存在产生富含蛋白质的蛋壳的细胞中。其次，寄生虫的主要跨膜铁转运体在寄生虫的外表面而不是在寄生虫的肠道中被发现，被认为参与了铁的吸收。这些蠕虫对铁的广泛营养依赖和铁摄取介体的表面位置增加了我们发现一种新系统的令人兴奋的可能性，该系统可能被用于疫苗或药物中介控制这些重要的人类寄生虫。如果我们能剖析血吸虫从宿主体内获取铁的途径，我们或许就能研制出阻断这一营养途径的疫苗，或者使用药物来阻断胚胎发育。这个项目是一个事实调查任务，询问这些寄生虫与宿主互动的覆盖层是否是新陈代谢铁的主要来源。我们证明存在于表面的分子将在小鼠疫苗试验中作为候选疫苗进行测试

This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular response induced by parasite eggs trapped in body organs is the major cause of chronic human disease. We have discovered two intriguing phenomena of iron metabolism in schistosomes. Firstly, schistosomes have a greater reliance on iron than many other organisms, storing a surfeit in cells that produce the protein-rich egg shell. Secondly, a major transmembrane iron transporter of the parasites, thought to be involved in the uptake of iron, is found on the parasite external body surface and not in the parasite intestine. The extensive nutritional dependence of these worms on iron and the surface location of mediators of iron uptake raise the exciting possibility that we have uncovered a novel system that might be exploited for vaccine or drug-mediated control of these significant human parasites. If we can dissect the pathways schistosomes use to derive iron from their hosts, we may be able to generate vaccines to block this nutritional pathway, or use drugs to block embryogenesis. This project is a fact-finding mission that asks if the host-interactive tegument of these parasites is a major source of metabolic iron. Molecules we demonstrate to be present on the surface will be tested as vaccine candidates in mouse vaccine trials