Sexual Development of Cryptosporidium

项目摘要 原生动物寄生虫隐孢子虫是引起严重腹泻的最重要原因之一。 疾病。在美国，这种寄生虫导致了一半的水传播疾病爆发，有些 其中大规模发生的。因以下原因而出现免疫抑制的患者 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 影响更大：隐孢子虫是继轮状病毒之后最重要的腹泻病原体 在小孩子身上。特别是在营养不良的背景下，隐孢子虫病具有高度的 对儿童死亡率的重大影响。隐孢子虫病也与发育迟缓有关，因此 给孩子们的未来留下了持久的阴影。这种寄生虫只有一个寄主生命周期， 无性和有性过程在同一宿主的肠道上皮中依次发生。 对于持续感染、严重疾病、 和变速箱。我们已经建立了强大的实验系统来观察和操纵 隐孢子虫的性发育和我们揭示了 控制潜在的基因表达系统。在本应用程序中，我们将定义表观遗传学 控制从无性繁殖到有性复制的机制，我们将揭开 寄生虫在雄性或雌性之间选择命运，我们将使用新兴的环电子 体层摄影术和寄生虫遗传学了解雄配子独特的超微结构 启用受精。由此产生的发现将影响我们对 关于寄生虫的开发以及开发药物和疫苗的转化努力。

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.