CRYPTOEXPORT: Exploring virulence and effector export in the intestinal parasite Cryptosporidium

隐孢子虫病是疟疾的主要病因，也是全球发病率和死亡率的主要原因。虽然疾病的负担主要由发展中国家的儿童承担，但隐孢子虫是一种普遍存在的肠道寄生虫，在世界各地经常爆发。已知细胞内病原体，如隐孢子虫，已经开发出复杂的输出系统，将效应子运输到其宿主细胞中，帮助病原体逃避检测和破坏。对于隐孢子虫，我们对它如何将效应子转运到宿主细胞以及这些效应子的作用一无所知。在这里，我们介绍了隐孢子虫丝氨酸重复蛋白，或SRP，一种新的主机输出的效应器，需要的毒力，并提出解决以下问题：如何SRP效应器的功能？在这里，我们将确定在整个寄生虫生命周期的亚细胞位置，这个关键的毒力因子，然后系统地解剖SRP功能，并建立这种功能是否是保守的跨不同物种的寄生虫。隐孢子虫如何输出效应子？在这里，我们将利用SRP来识别在该输出途径中发挥作用的其他输出效应子和寄生虫因子，包括隐孢子虫独特和未知的运输机制。输出效应子如何影响隐孢子虫的毒力和免疫力？在这里，我们将使用我们的小鼠感染模型来研究输出效应子如何促进寄生虫负担，疾病病理学和宿主免疫反应。

Cryptosporidiosis is a leading cause of diarrheal disease and a major contributor to global morbidity and mortality. Although the burden of disease is primarily carried by children in developing countries, Cryptosporidium is a ubiquitous intestinal parasite with frequent outbreaks around the world. Intracellular pathogens, such as Cryptosporidium, are known to have developed sophisticated export systems that transport effectors into their host cell, helping the pathogen to evade detection and destruction. For Cryptosporidium, nothing is known about how it transports effectors into its host cell and what these effectors do. Here, we introduce the Cryptosporidium serine repeat protein, or SRP, a novel host-exported effector that is required for virulence and propose to address the following questions: How does the SRP effector function? Here we will determine the subcellular location of this critical virulence factor throughout the parasite life cycle, then systematically dissect SRP function and establish whether this function is conserved across different species of the parasite. How does Cryptosporidium export effectors? Here we will leverage SRP to identify other exported effectors and parasite factors that play a role in this export pathway, including the unique and unknown transport machinery of Cryptosporidium. How do exported effectors influence Cryptosporidium virulence and immunity? Here we will use our mouse model of infection to investigate how exported effectors contribute to parasite burden, disease pathology, and the host immune response.