Critical early events at the mucosal/worm interface following infection fo sheep with the abomasal nematode Teladorsagia circumcincta

摘要寄生性胃肠炎(PGE)是由毛囊线虫引起的一种常见的绵羊全身性疾病，其主要致病原为圆环毛囊线虫(Teladorsagia Circincta)。从生产的角度来看，这种综合症会导致食物利用率受损、生长速度低下以及屠体和羊毛质量差，简而言之，这会给生产者造成经济损失，损害经济生存能力。由于目标线虫中迅速出现抗药性，依赖于使用驱虫剂的控制正在失败。接种疫苗是一种可行的替代方案，但由于缺乏对传入幼虫的宿主-寄生虫相互作用的了解，这一发展受到阻碍。幼虫是绵羊免疫的主要影响因素。随着这种反应的发展，人们认为它会导致幼虫发育受阻，这是导致断奶羔羊患病的一个主要因素。在这里，我们将寻求定义感染宿主位置(真正的胃或皱胃)与传入幼虫之间的分子相互作用，目的是确定驱逐蠕虫所需的宿主机制，以及刺激这些蠕虫或成为它们的靶标的蠕虫蛋白。我们将定义宿主基因在皱胃表层的表达，以响应传入的幼虫，并独特地将这一分析与幼虫中的等价物进行比较。其目的是将宿主对寄生虫的关键早期反应与寄生虫基因表达的发育变化联系起来，其中一些变化可能是由宿主诱导的，并在宿主体内形成抗寄生虫免疫的情况下影响寄生虫的生存策略。这项工作将使我们能够确定潜在的候选疫苗，并提供优化疫苗交付所需的基本信息，使接种疫苗的控制更近一步。

SUMMARY Parasitic gastroenteritis (PGE), caused by trichostrongylid nematodes, is the most commonly diagnosed systemic disease of sheep in the U.K. The principal causative nematode (worm) is the abomasal parasite Teladorsagia circumcincta. From a production perspective, the syndrome causes impaired food utilisation, poor growth rates as well as poor carcass and fleece quality, in short, economic loses for the producer which compromise economic viability. Control, dependent on the use of anthelmintics, is failing due to the rapid emergence of drug resistance in the target nematodes. Vaccination is a feasible alternative but development is hampered by a lack of knowledge of the host-parasite interaction to incoming larvae, a prime effector of immunity in sheep. As this response develops, it is thought to induce arrested larval development, a factor which makes a major contribution to disease in the weaned young lamb. Here we will seek to define the molecular interactions between the host site of infection (the true stomach or abomasum) and the incoming larvae, the purpose being to identify the host mechanisms required to expel the worms and the worm proteins stimulating these or being targeted by them. We will define host gene expression in the abomasal surface layer in response to incoming larvae and, uniquely, parallel this analysis with the equivalent in the larvae. The purpose is to correlate key early host responses to the parasite with developmental changes in parasite gene expression, some of which are likely to be induced by the host and effect a parasite survival strategy in the face of developing anti-parasite immunity in the host. This work will allow us to identify potential vaccine candidates and provide basic information required to optimise vaccine delivery bringing control by vaccination a step closer.