Abstract
As of 2019 there were nearly 500,000 people infected with Ascaris, and in pigs Ascaris infection is also a global issue. With the high use of a limited number of drugs to combat ascariasis the development of resistance is always a worry. This work focused on trying to understand the potential for the development of anthelmintic resistance in Ascaris.
By surveying British pig farms and using national post-mortem datasets this work has highlighted differences in Ascaris suum prevalence across Britain that may be associated with region and rearing methods.
This study characterised the repertoire of Ascaris β-tubulins and investigated the roles they play in the development of benzimidazole resistance. Using experimental and transcriptomic data the expression profiles of multiple β-tubulin genes were determined to highlight the isotypes most likely to play a role in benzimidazole mechanisms of action.
Genetic screening of these isotypes from Ascaris samples across the world showed that none possessed the resistance-associated mutations typically seen in benzimidazole resistant nematodes.
Using in silico simulations this work showed how mutations in β-tubulins can alter drug interactions and potentially lead to benzimidazole resistance, and identified key residues involved in benzimidazole binding. By applying the same methods to other parasites of importance this study highlighted differences between groups of nematodes which may explain the difference seen in the development of resistance in these parasites.
The research presented has demonstrated that Ascaris possess a larger repertoire of β-tubulins than other nematodes, but they still interact with benzimidazoles in a similar manner. Therefore, it would be possible for the common resistance-associated mutations to cause anthelmintic resistance.
This research has led to the publishing of two articles, with another under review and one more to be submitted in the future. It has also contributed to another publication not included in this thesis.