Sexual Development of Cryptosporidium

原生动物寄生虫隐孢子虫是严重疟疾的最重要原因之一 这种疾病在世界各地表现出不同的流行病学。在美国 暴发与受污染的娱乐和饮用水有关， 规模因HIV/AIDS、器官移植或 癌症处于最严重的危险之中。全球公共卫生影响更大：轮状病毒之后， 隐孢子虫是小儿最重要的肠道病原体。在婴儿中， 特别是在营养不良的情况下，隐孢子虫病对 幼儿总体死亡率和发病率。隐孢子虫病也与发育迟缓有关， 给孩子们的未来留下了永久的阴影。没有疫苗，只有一种药物 边际效益。这种寄生虫有一个单一的宿主生命周期，既有无性过程，也有有性过程 在同一宿主的肠上皮中依次发生。完成这一发展 持续感染、严重疾病和病原体传播需要程序。尽管 生命周期对药物和疫苗开发的明显重要性，我们目前的 理解是基本的。这是一个非常复杂的生物现象-- 在这里有很多发现-我们期待着对基础和翻译的见解 意义我们最近开创了一个隐孢子虫的遗传系统， 这个项目在分子和细胞水平上剖析生命周期。根据这项建议，我们将 开发严格的分子标记和分析，通过无性和有性发育 阶段，揭示阶段特异性基因表达，并发现执行功能的机制 和生命周期中的进展。缺乏培养隐孢子虫的有效系统， 长期阻碍进展。我们将明确体外发育在哪里脱轨， 这些见解将指导今后的工作，以促进一个持续的文化模式。

The protozoan parasite Cryptosporidium is one of the most important causes of severe diarrheal disease, and the disease manifests itself with varied epidemiology around the world. In the U.S. outbreaks are linked to tainted recreational and drinking water and have occurred at massive scale. Patients suffering from immunosuppression due to HIV/AIDS, organ transplantation, or cancer are in gravest danger. The global public health impact is even larger: after Rotavirus, Cryptosporidium is the most important diarrheal pathogen in small children. In infants, in particular in the context of malnutrition, cryptosporidiosis has a highly significant imprint on overall early childhood mortality and morbidity. Cryptosporidiosis is also linked to stunting, thus leaving a lasting shadow on the future of children. There are no vaccines and only a single drug of marginal efficacy. This parasite has a single host life cycle, both asexual and sexual processes occur sequentially in the intestinal epithelium of the same host. Completion of this developmental program is required for continued infection, severe disease, and spread of the pathogen. Despite the obvious importance of the lifecycle for drug and vaccine development, our current understanding is rudimentary. This is a biological phenomenon of fascinating complexity – there is much to discover here – and we expect insights of fundamental as well as translational significance. We have recently pioneered a genetic system for Cryptosporidum that we will use in this project to dissect the lifecycle at the molecular and cellular level. Under this proposal we will develop rigorous molecular markers and assays for development through asexual and sexual stages, reveal stage specific gene expression, and discover the mechanisms that execute function and progression through the lifecycle. Lack of efficient systems to culture Cryptosporidium has long hampered progress. We will define where specifically in vitro development derails, and these insights will guide future work to facilitate a continuous culture model.