The role of GPI-linked surface proteins in site-specific tropism of Eimeria parasites and the potential of these proteins for novel therapies.

显微镜下的单细胞寄生虫可引起人类和家畜的多种疾病，其中一些非常严重。我们正在研究艾美耳球虫寄生虫，这种寄生虫会导致家禽肠炎，如果感染得不到控制，会导致非常高的死亡率。有七种不同的艾美耳球虫感染鸡，每一种都生长在鸡肠道的不同部位，迅速产生数百万种新的寄生虫，这些寄生虫在粪便中排泄并感染邻近的鸟类。从感染中恢复的鸟类对它们感染的物种产生天然免疫力，但不幸的是，它们仍然对其他六种物种的感染非常敏感。我们对一种寄生虫--柔嫩艾美耳球虫（Eimeria tenella）做了大量的研究，发现寄生虫的表面被膜由宿主容易识别的分子（蛋白质）组成，在感染过程中会发生变化，因此寄生虫的后期阶段不再具有与早期阶段相同的被膜。我们也简要地观察了其他艾美耳球虫的表面被膜，发现它们由与艾美耳球虫的被膜相关但不同的蛋白质组成。tenella。我们认为，每种寄生虫的表面涂层的特定性质可能是重要的，在确定每种寄生虫的肠道的哪一部分，物种之间的外套的可变性质可以解释为什么宿主免疫力只对一个单一的物种有效的时间。我们还认为，在感染过程中改变的外套可能有助于寄生虫完成自己的生命周期，而不会被防止再次感染的宿主免疫力破坏太多。在这个建议中，我们计划进行实验，以确定我们的想法是否正确。首先，我们将更详细地观察第二种艾美球虫寄生虫（巨型艾美球虫）的表面外壳，一旦我们确切地知道它是由哪些蛋白质组成，我们将开始使用遗传操作来做一些“外壳交换”实验。我们将使柔嫩艾美耳球虫早期阶段穿上巨型艾美耳球虫早期阶段的外衣，然后确定这种混合寄生虫在鸡肠道内的生长位置。我们还将测试感染了这种混合寄生虫的鸡是否只对一种或两种物种产生免疫力，如果答案是两种物种，我们将尝试利用这些表面涂层作为疫苗。我们还将研究如果使柔嫩艾美耳球虫的后期阶段与早期阶段穿着相同的外套会发生什么，因为我们预计感染这种寄生虫的鸡可能会遭受比正常寄生虫严重得多的感染，并且这可能是一种生产确定的减毒疫苗的方法。

Microscopic single-celled parasites can cause many types of disease in man and domestic animals, some of them very serious. We are working on Eimeria parasites, which cause enteritis in domestic chickens that can lead to very high death rates if infections are not controlled. There are seven different species of Eimeria that infect chickens and each one of these grows in a different part of the chicken gut, rapidly producing many millions of new parasites that are excreted in the faeces and infect neighbouring birds. Birds that recover from infection develop natural immunity to the species they were infected with but unfortunately they remain fully susceptible to infections with the other six species. We have done a lot of work one species of the parasite, Eimeria tenella, and have discovered that the surface coat of the parasite, which is composed of molecules (proteins) that the host easily recognises, changes during the course of infection so that the later stages of the parasite no longer have the same coat as the early stages. We have also taken a brief look at the surface coats of some other species of Eimeria and find that are composed of related, but different, proteins to the coat of E. tenella. We think that the specific nature of the surface coat of each parasite may be important in determining which part of the gut each parasite goes to and that the variable nature of the coat between species may explain why host immunity is only effective against a single species at a time. We also think that having a coat that changes during infection may help the parasite to complete its own life cycle without being damaged too much by the host immunity that prevents reinfection. In this proposal we plan to carry out experiments to find out if we are on the right track with our thoughts First of all we will take a more detailed look at the surface coat of a second Eimeria parasite (Eimeria maxima) and once we know precisely which proteins it is composed of we will begin to use genetic manipulation to do some 'coat swap' experiments. We will make the early stage of Eimeria tenella wear the coat of the early stage of Eimeria maxima and then determine whereabouts within the chicken gut this mixed parasite grows. We will also test whether chickens that have been infected with this mixed parasite develop immunity to just one or to both of the species and if the answer is to both species we will try to exploit the use of these surface coats as vaccines. We will also look at what happens if the later stages of Eimeria tenella are made to wear the same coat as the early stages, as we expect that chickens infected with this type of parasite are likely to suffer a much less severe infection that with a normal parasite and again this may be a way to produce a defined, attenuated vaccine.