The benzimidazoles are one of the most important anthelmintic drug classes used to control parasitic nematodes in domestic animals and humans. They have been intensively used in the livestock sector for over 30 years resulting in widespread resistance in small ruminant parasite species such as Haemonchus contortus. The work presented in this thesis investigates the molecular genetics of benzimidazole resistance in H. contortus and the closely related species Haemonchus placei. The major focus is on India and Pakistan, two regions that were considered to be potentially informative as to how resistance mutations arise and spread due to resistance being at a relatively early stage. Chapter II, explores parasite populations in small ruminants in the Punjab region of Pakistan showing that co-infections with the two species were relatively common and that interspecies F1 hybrids were present in several populations. This raises the possibility of introgression of anthelmintic resistance genes from one species to another. Chapter III, presents a study in southern India which provides phylogenetic evidence that the F200Y (TAC) mutation has arisen multiple independent times in the region. In contrast, the E198A (GCA) mutation appears to have arisen and spread from a single origin. This is the first genetic evidence of the spread of an anthelmintic resistance mutation between locations for any parasitic nematode species to date. Chapter IV compares the molecular genetics of benzimidazole resistance in H. contortus populations under intense drug selection pressure on small ruminant government farms in Pakistan with parasite populations that are under minimal selection pressure in neighbouring rural areas. Overall, the results of this work are consistent with the hypothesis that the F200Y (TAC) isotype-1 -tubulin mutation appears by recurrent mutation during selection as well as being present in the standing genetic variation present prior to the onset of selection. Finally, Chapter V, presents evidence that benzimidazole resistance is at an early stage of emergence in H. placei from cattle in the southern and mid-west USA. This raises a significant concern that clinical resistance could emerge quite quickly as more benzimidazoles are used in cattle as is the current trend.
|Publication status||Published - 2015|