Functional validation of novel levamisole resistance marker S168T in Haemonchus contortus

Antonopoulos, A., Charvet, C. L., Maitland, K. , Doyle, S. R., Neveu, C. and Laing, R. (2024) Functional validation of novel levamisole resistance marker S168T in Haemonchus contortus. International Journal for Parasitology: Drugs and Drug Resistance, 24, 100524. (doi: 10.1016/j.ijpddr.2024.100524) (PMID:38346379) (PMCID:PMC10867575)

Abstract

Recently, a S168T variant in the acetylcholine receptor subunit ACR-8 was associated with levamisole resistance in the parasitic helminth Haemonchus contortus. Here, we used the Xenopus laevis oocyte expression system and two-electrode voltage-clamp electrophysiology to measure the functional impact of this S168T variant on the H. contortus levamisole-sensitive acetylcholine receptor, L-AChR-1.1. Expression of the ACR-8 S168T variant significantly reduced the current amplitude elicited by levamisole compared to acetylcholine, with levamisole changing from a full to partial agonist on the recombinant L-AChR. Functional validation of the S168T mutation on modulating levamisole activity at the receptor level highlights its critical importance as both a mechanism and a marker of levamisole resistance.

• Item Type: Articles
• Additional Information: This work was funded by a BBSRC International Partnership grant [BB/W510658/1]. CN and CLC are supported by the Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE). SRD is supported by a UKRI Future Leaders Fellowship [MR/ T020733/1] and the Wellcome Trust (UK) through core funding to the Wellcome Sanger Institute (UK) [206194]. RL is supported by a Wellcome Clinical Research Career Development Fellowship [216614/Z/19/ Z] and a University of Glasgow Lord Kelvin Adam Smith Fellowship (LKAS).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Laing, Dr Roz and Antonopoulos, Mr Alistair and Maitland, Ms Kirsty
• Authors: Antonopoulos, A., Charvet, C. L., Maitland, K., Doyle, S. R., Neveu, C., and Laing, R.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: International Journal for Parasitology: Drugs and Drug Resistance
• Publisher: Elsevier
• ISSN: 2211-3207
• ISSN (Online): 2211-3207
• Copyright Holders: Copyright: © 2024 The Authors
• First Published: First published in International Journal for Parasitology: Drugs and Drug Resistance 24: 100524
• Publisher Policy: Reproduced under a Creative Commons licence

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
306505		Hitting a moving target: genomic and metabolic approaches to improve anthelmintic use in evolving helminth populations	Rosalind Laing	Wellcome Trust (WELLCOTR)	216614/Z/19/Z	MVLS - Research Facilities