Specificity in host carbohydrate-apicomplexan recognition

顶复合体门包含一些最广泛的人类和动物的原生动物寄生虫。主要成员包括疟原虫、艾美耳球虫、犬新孢子虫和刚地弓形虫。弓形虫不仅是研究其他顶复合体寄生虫的主要模型，它本身也是一种重要的病原体，可引起严重的播散性疾病。艾美耳球虫是一组在肠细胞内发育的非常成功的细胞内原生动物寄生虫。它们是引起鸡肠道球虫病的原因，是现代家禽养殖中最重要的经济疾病之一。犬新孢子虫已成为牛和狗的重要全球性病原体。犬奈瑟菌被认为是奶牛繁殖失败的主要诊断原因，受感染的牛流产的可能性高达7倍。顶复体的感染是通过快速和强制入侵宿主细胞在宿主体内建立的。在这一过程的第一阶段分泌的蛋白质参与了宿主细胞表面的顶端附着，并与寄生虫放线肌球蛋白系统形成连接，从而提供了驱动入侵的平台——这些蛋白质被称为微素蛋白（mic）。我们在该蛋白家族中发现了一个与宿主碳水化合物相互作用的新区域，该区域存在于艾美耳球虫和犬链球菌的mic中。我们将其命名为“微金属粘合重复区”（MARRs）。我们计划研究mic如何区分宿主配体的一些基本方面，这将为寄生虫在分子水平上如何工作提供新的信息。我们的具体目标是确定从三种不同的顶络合物与同源配体络合物的marr的结构。我们的研究提供的结构信息将使我们能够对它们如何区分不同的细胞类型做出新的假设。然后我们将设计新的实验来检验这些假设。我们的工作应该为揭示抗菌策略开发的新途径提供基础。

The phylum Apicomplexa contains some of the most widespread protozoan parasites of humans and animals. Key members include Plasmodium spp., Eimeria spp., Neospora caninium and Toxoplasma gondii. Not only has T. gondii emerged as the principal model for the study of other apicomplexa parasites it is an important pathogen in its own right, causing severe disseminated disease. Eimeria are a group of highly successful intracellular protozoan parasites that develop within enterocytes. They are the cause of intestinal Coccidiosis in chickens, which is one of the economically most important diseases in modern poultry farming. Neospora caninum has emerged as global pathogen of major significance in cattle and dogs. N. caninum is recognised as the major diagnosed cause of reproductive failure in dairy cattle and infected cattle are up to seven times more likely to abort. Infection by apicomplexans is established in the host by rapid and forced invasion of host cells. Proteins secreted at the first stage of this process, participate in apical attachment to host cell surfaces and the formation of a connection with the parasite actinomyosin system, thereby providing the platform from which to drive invasion - these are called microneme proteins (MICs). We have identified a novel region within this family of proteins that interacts with host carbohydrates and is present in MICs from Eimeria and N. caninum. We have named this the 'Micronemal Adhesive Repeat Regions' (MARRs). We plan to investigate some fundamental aspects of how MICs discriminate host ligands, which will provide new information on how the parasite works at the molecular level. Our specific objectives are to determine the structures of MARRs from three different apicomplexans in complex with cognate ligands. The structural information provided by our studies will allow us to make new hypotheses about how they discriminate between different cell types. We will then design new experiments to test these hypotheses. Our work should provide a foundation that may reveal new pathways to the development of antimicrobial strategies.