Sexual Development of Cryptosporidium

项目摘要 原生动物寄生虫隐孢子虫是严重疟疾的最重要原因之一 疾病在美国，这种寄生虫是造成所有水传播疾病爆发的一半原因， 大规模的发生。免疫抑制患者， 艾滋病毒/艾滋病、器官移植或癌症处于最严重的危险之中。全球公共卫生 影响甚至更大：在轮状病毒之后，隐孢子虫是最重要的疟疾病原体 在幼儿中。特别是在营养不良的情况下，隐孢子虫病具有高度的 对儿童死亡率有重大影响。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。这种寄生虫只有一个宿主生命周期， 在同一宿主的肠上皮中，无性和有性过程依次发生。 持续感染，严重疾病， 和传输。我们已经建立了强大的实验系统来观察和操纵 隐孢子虫的性发育，我们解开了机制的关键要素， 控制潜在的基因表达系统。在本申请中，我们将定义表观遗传 控制从无性繁殖到有性繁殖的过渡机制，我们将揭开 寄生虫在男性或女性之间选择命运，我们将使用新兴的低温电子 断层扫描和寄生虫遗传学来了解雄配子独特的超微结构 使受精。由此产生的发现将影响我们对以下问题的基本理解： 寄生虫的发展和转化的努力，开发药物和疫苗。

Project Abstract The protozoan parasite Cryptosporidium is one of the most important causes of severe diarrheal disease. In the U.S. this parasite is responsible for half of all waterborne disease outbreaks, some of which 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 particular in the context of malnutrition, cryptosporidiosis has a highly significant imprint on childhood mortality. Cryptosporidiosis is also linked to stunting, thus leaving a lasting shadow on the future of children. This parasite has a single host life cycle, 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 transmission. We have built robust experimental systems to observe and manipulate the sexual development of Cryptosporidium and we unraveled key elements of the mechanisms that control the underlying gene expression systems. In this application we will define the epigenetic mechanisms that govern transition from asexual to sexual replication, we will unravel how the parasites choses between a male or female fate, and we will use emerging cyro-electron tomography and parasite genetics to understand how the unique ultrastructure of male gametes enables fertilization. The resulting findings will impact on our fundamental understanding of parasite development and on translational efforts to develop drugs and vaccines.