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

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.

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. 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, which makes a major contribution to disease in weaned young lambs. Here, we seek to define the molecular events occuring in the earliest phase of infection, within the first hours of incoming larvae contacting the epithelial surface of the abomasum. The aim is to improve our understanding of the early host/parasite interaction in order to identify key immune effectors responses and the parasite proteins stimulating/modulating them. The ultimate aim is targeted vaccine development where key parasite pathways are defined, as well as the host response required to neutralise it. We will exploit existing ovine cDNA arrays and T. circumcincta EST datasets to perform a parallel analysis of gene expression in naïve, immune and immune-waning abomasal mucosae and incoming L3 larvae, using direct challenge in vivo (gastric fistulae) or in vitro (abomasal explants). Bioinformatic tools will identify key genes and seek correlates between host/parasite gene expression. We will also monitor the host response by proteomic analyses of abomasal mucus to identify potential key early effectors of worm impairment and subsequent exclusion/expulsion. These parallel analyses represents a unique approach which we anticipate will allow us to draw firm conclusions about the early epithelial responses contributing to rejection and/or establishment of incoming larvae.