Using C. elegans to produce proteins from parasitic nematodes for research and therapeutic use

几种寄生虫感染人类，并导致象皮病和河盲症等令人衰弱的疾病。为了生存，寄生虫需要逃离人类的免疫系统，因此它们已经进化成分泌蛋白质，干扰免疫反应。如果我们能够了解这些蛋白质是如何工作的，我们就可以利用这些知识来治疗由免疫系统过度活跃引起的疾病，如关节炎、湿疹、哮喘和肠易激综合征。为此，我们在了解其中一种名为ES-62的蛋白质的作用机制方面取得了重大进展。这一进展之所以成为可能，是因为我们可以在实验室里从沙土鼠体内生长的一种寄生线虫--刺五加线虫中提取这种蛋白质。然而，我们每年需要为这项工作牺牲数百只实验室啮齿动物，而且既昂贵又耗时。此外，必须牺牲更多的动物才能生产出足够的ES-62来进行临床试验。我们建议通过使用一种名为秀丽线虫的自由生活线虫来产生这种蛋白质来取代啮齿动物的使用。这种蠕虫可以在实验室里大量生长，只需用细菌作为食物来源进行培养即可。线虫被广泛用于生物学研究，已经有了既定的方法将能够从其他动物中生产蛋白质的基因引入其中。这对来自相关动物(如其他线虫)的蛋白质尤其有效。此外，我们已经开发了一种新的方法，可以方便地从线虫中提纯ES-62，我们将进行检查，以确保我们生产的蛋白质具有与寄生虫制成的蛋白质相同的性质。我们的建议不仅是在ES-62的生产中直接取代实验室动物，而且还表明有可能大量生产这种蛋白质，用于治疗和商业目的。此外，这项技术将不仅限于生产ES-62，因为我们的战略还有可能从蠕虫中生产免疫抑制蛋白，这些蠕虫是人类寄生虫，如导致上述疾病的寄生虫。总体而言，我们的研究将使这些寄生虫的蛋白质能够被生产和表征，从而进一步了解免疫系统如何被修改以达到治疗目的。

Several species of parasitic worm infect human beings and cause debilitating diseases such as elephantiasis and river blindness. To survive the parasites need to escape the human immune system, and so they have evolved to secrete proteins that interfere with immune responses. If we could understand how these proteins work we could use the knowledge to treat diseases caused by an overactive immune system such as arthritis, eczema, asthma and irritable bowel syndrome. Towards this, we have made significant progress in understanding the mechanism of action of one of these proteins called ES-62. This progress has been made possible because we can make this protein in the laboratory from Acanthocheilonema viteae, a parasitic nematode worm that grows in gerbils. However, we need to sacrifice hundreds of lab rodents each year for this work, and it is also both expensive and time consuming. Moreover, a much larger number of animals would have to be sacrificed to produce enough ES-62 to be able to undertake a clinical trial. We propose to replace the use of the rodents by producing this protein using a free-living nematode called Caenorhabditis elegans. This worm can be grown in a lab in large amounts simply by culturing it with bacteria as a food source. C. elegans is used widely for biological research and there are established methods to introduce genes into it capable of producing proteins from other animals. This works particularly well with proteins from related animals such as other nematode worms. Furthermore we have developed a new method that should facilitate ready purification of ES-62 from C. elegans and we will check to ensure that the protein we produce has the same properties as the protein made from the parasitic worms. Our proposal is not only to directly replace laboratory animals in the manufacture of ES-62 but also to show that it is possible to produce the protein in large enough quantities to be used for therapeutic and commercial purposes. Furthermore, the technology will not be limited to manufacturing ES-62 as our strategy also has the potential to produce immunosuppressive proteins from worms that are human parasites such as those that cause the diseases referred to above. Overall our research will enable proteins from these parasites to be produced and characterised, leading to further understanding of how the immune system can be modified for therapeutic purposes.