Functional validation of the truncated UNC-63 acetylcholine receptor subunit in levamisole resistance

Levamisole is a broad-spectrum anthelmintic which permanently activates cholinergic receptors from nematodes, inducing a spastic paralysis of the worms. Whereas this molecule is widely used to control parasitic nematodes impacting livestock, its efficacy is compromised by the emergence of drug-resistant parasites. In that respect, there is an urgent need to identify and validate molecular markers associated with resistance. Previous transcriptomic analyses revealed truncated cholinergic receptor sub-units as potential levamisole resistance markers in the trichostrongylid nematodes Haemonchus contor-tus, Telodorsagia circumcincta and Trichostrongylus colubriformis. In the present study we used the Xenopus oocyte, as well as the free-living model nematode Caenorhabditis elegans, as heterologous expres-sion systems to functionally investigate truncated isoforms of the levamisole-sensitive acetylcholine receptor (L-AChR) UNC-63 subunit. In the Xenopus oocyte, we report that truncated UNC-63 from C. ele-gans has a strong dominant negative effect on the expression of the recombinant C. elegans L-AChRs. In addition, we show that when expressed in C. elegans muscle cells, truncated UNC-63 induces a drastic reduction in levamisole susceptibility in transgenic worms, thus providing the first known functional val-idation for this molecular marker in vivo.& COPY; 2023 Published by Elsevier Ltd on behalf of Australian Society for Parasitology.

Automated summary

Levamisole is a broad-spectrum anthelmintic used to control parasitic nematodes impacting livestock, but its efficacy is compromised by drug-resistant parasites. This study investigates truncated cholinergic receptor sub-units as potential levamisole resistance markers in nematodes. The researchers used Xenopus oocyte and Caenorhabditis elegans as expression systems to functionally investigate these markers. They found that truncated UNC-63 induces a reduction in levamisole susceptibility, providing the first functional validation for this molecular marker.