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

隐孢子虫病是腹泻疾病的主要原因，也是导致全球发病率和死亡率的主要因素。尽管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。众所周知，细胞内的病原体，如隐孢子虫，已经开发出复杂的出口系统，将效应物运送到宿主细胞中，帮助病原体逃避检测和破坏。对于隐孢子虫，人们对它如何将效应器输送到宿主细胞以及这些效应器的作用一无所知。在这里，我们介绍了隐孢子虫丝氨酸重复蛋白，或SRP，一种新的宿主输出的毒力所需的效应器，并建议解决以下问题：SRP效应器如何发挥作用？在这里，我们将确定这一关键毒力因子在整个寄生虫生命周期中的亚细胞位置，然后系统地剖析SRP功能，并确定该功能是否在不同种类的寄生虫中保守。隐孢子虫如何输出效应物？在这里，我们将利用SRP来确定在这一出口途径中发挥作用的其他出口效应物和寄生虫因子，包括隐孢子虫独特的和未知的运输机制。出口效应物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出口效应器如何促进寄生虫负担、疾病病理和宿主免疫反应。

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.