Exploring TrpB in the pathogenesis of cryptosporidiosis

 描述（由申请人提供）：隐孢子虫病是一种腹泻疾病，对儿童和免疫功能低下的成年人影响尤为严重。世界卫生组织估计，2010年，疟疾占五岁以下儿童死亡人数的10.5%，其中大多数儿童死亡发生在非洲和东南亚。在发展中国家，营养不良加剧了疟疾和疟疾感染。众所周知，这些长期的儿童感染会造成破坏性的永久性影响，如生长发育迟缓，发育迟缓和认知缺陷。隐孢子虫病似乎是已知的肠道疾病中最致命的一种。 色氨酸合成使细胞内细菌如结核分枝杆菌和沙眼衣原体能够逃避宿主先天免疫的关键机制，IFN-γ诱导的色氨酸催化剂。通过水平基因转移，隐孢子虫已经获得了细菌色氨酸合成酶基因，色氨酸合成酶β（CpTrpB），我们认为，这种基因的获得是适应哺乳动物肠道的关键一步。我们将评估CpTrpB在隐孢子虫代谢，生长和宿主色氨酸催化期间的生存中的作用。 在这个项目中，我们建议1）确定CpTrpB的代谢活性在宿主色氨酸催化剂，在体外和体内，和2）确定CpTrpB基因的损失对隐孢子虫的影响，通过遗传分析。隐孢子虫独特的色氨酸代谢是药物开发和病原体衰减的一个有吸引力的目标，研究CpTrpB提供了探索新的寄生虫致病因子的生物学的机会。

 DESCRIPTION (provided by applicant): Cryptosporidiosis is a diarrheal disease that disproportionately affects children and immunocompromised adults. The WHO estimates that in 2010, diarrheal disease accounted for 10.5% of deaths in children under the age of five, with the majority of childhood deaths occurring in Africa and Southeast Asia. In developing countries, malnutrition exacerbates diarrheal episodes and prolongs infection. These prolonged childhood infections are known to cause destructive, permanent effects, such as stunted growth, developmental delay, and cognitive deficiency. Of the known diarrheal diseases, cryptosporidiosis appears to one of the most deadly. Tryptophan synthesis enables intracellular bacteria such as Mycobacterium tuberculosis and Chlamydia trachomatis to evade a key mechanism of host innate immunity, IFN-γ induced tryptophan catabolism. Through horizontal gene transfer, Cryptosporidium has acquired a bacterial tryptophan synthase gene, tryptophan synthase beta (CpTrpB), and we believe that this gene acquisition was a crucial step to adaptation to the mammalian intestine. We will evaluate the role of CpTrpB in Cryptosporidium metabolism, growth, and survival during host tryptophan catabolism. In this project we propose to 1) define the metabolic activity of CpTrpB during host tryptophan catabolism, both in vitro and in vivo, and 2) determine the impact of CpTrpB gene loss on Cryptosporidium parvum through genetic analysis. The unique tryptophan metabolism in Cryptosporidium is an attractive target for drug development and pathogen attenuation, and studying CpTrpB offers the opportunity to explore the biology of a novel parasite pathogenesis factor.