The sensory amphidial structures of Caenorhabditis elegans are involved in macrocyclic lactone uptake and anthelmintic resistance

Page, A. P. (2018) The sensory amphidial structures of Caenorhabditis elegans are involved in macrocyclic lactone uptake and anthelmintic resistance. International Journal for Parasitology, 48(13), pp. 1035-1042. (doi: 10.1016/j.ijpara.2018.06.003) (PMID:30253131) (PMCID:PMC6237615)

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Abstract

Parasitic nematodes represent formidable pathogens of humans, livestock and crop plants. Control of these parasites is almost exclusively dependent on a small group of anthelmintics, the most important of which belong to the macrocyclic lactone class. The extensive use of these drugs to control the ubiquitous trichostrongylid parasites of grazing livestock has resulted in the emergence of both single and multi-drug resistance. The expectation is that this resistance will eventually occur in the human parasites such as the common and debilitating soil transmitted nematodes and vector-borne filarial nematodes. While the modes of action of anthelmintics such as ivermectin (IVM), have been elucidated, notably in the model nematode Caenorhabditis elegans, the molecular nature of this resistance remains to be fully determined. Here we show that the anterior amphids play a key role in IVM uptake and mutations in these sensory structures result in IVM resistance in C. elegans. Random genetic mutant screens, detailed analysis of existing amphid mutants and lipophilic dye uptake indicate that the non-motile ciliated amphid neurons are a major route of IVM ingress; the majority of the mutants characterized in this study are predicted to be involved in intraflagellar transport. In addition to a role in IVM resistance, a subset of the amphid mutants are resistant to the non-related benzimidazole class of anthelmintics, raising the potential link to a multi-drug resistance mechanism. The amphid structures are present in all nematodes and are clearly defined in a drug-sensitive strain of Haemonchus contortus. It is predicted that amphidial drug uptake and intraflagellar transport may prove to be of significance in the development of single and multi-drug resistance in the nematode pathogens of veterinary and human importance.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Page, Professor Tony
Authors: Page, A. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:International Journal for Parasitology
Publisher:Elsevier
ISSN:0020-7519
ISSN (Online):1879-0135
Published Online:22 September 2018
Copyright Holders:Copyright © 2018 The Author
First Published:First published in International Journal for Parasitology 48(13): 1035-1042
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
3032250Resistance in Agriculture: Investigation of Anthelmintic Drug Uptake and Resistance Mechanisms in Gastrointestinal Nematode Parasites of LivestockAntony PageBiotechnology and Biological Sciences Research Council (BBSRC)BB/R00711X/1Vets Farm- Farm Animal Clinical Sciences