Pathophysiology and immunomodulation associated with Haemonchus contortus infection : a dissertation presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Massey University, Palmerston North, New Zealand

The aim of this project was to investigate host-parasite interactions, which might lead to alternate strategies to control the sheep abomasal nematode Haemonchus contortus. The project focused on two aspects of host parasite interactions: the initiation of host pathology and suppression of host immune responses associated with the onset of infection. Adult H. contortus ES products increased the permeability of Caco-2 cell monolayers and this increase could be blocked by single chain antibodies against ES products displayed on phage. Recombinant H. contortus enolase may be one of the active components of ES as it mimicked the action of ES products on Caco-2 cells. This is the first study of immunomodulation by adult H. contortus ES products of the phenotypic and functional properties of human monocyte-derived dendritic cells (mdDCs). Incubation with ES products resulted in semi-maturation of mdDCs, with weak up-regulation of the co-stimulatory molecules CD40 and CD80 and increased surface expression of the tolerogenic markers CD32, CD305 and galectin-1. The highly variable responses of mdDCs of individual donors biased the group data, particularly in response to co-stimulation with ES products and LPS. This highlights genetic diversity in the immune system and possible difficulties in developing worm-based therapies. The blastogenic activities of cells from lymph nodes collected from two groups of infected and vaccinated sheep were measured by 3H-thymidine uptake after exposure to ConA or ES products. The Stimulation Index (SI) with ConA was 1 0-fold higher in cells from the older animals. Cells only from younger infected sheep had a reduced response to ConA and vaccinated groups with reduced parasite burdens had the highest Sl. There was little response to ES products in older sheep, but in younger animals there was a trend for lymphocyte Sl to be greater with 10% ES in sheep with the fewest parasites. These experiments show that H. contortus ES products may facilitate the initiation of host pathology and the potential to modulate responses of dendritic and lymph node cells during parasitism. Further identification of the specific ES components responsible may allow disruption of their actions, resulting in resilient and immune sheep