TY - ABST

T1 - A molecular target of oxantel in whipworms

AU - Hansen, Tina Vicky Alstrup

AU - Klærke, Dan Arne

AU - Cirera, Susanna

AU - Callø, Kirstine

AU - Courtot, Elise

AU - Grencis, Richard K.

AU - Issouf, Mohamed

AU - Martin, Richard

AU - Neveu, Cedric

AU - Charvet, Claude

PY - 2023

Y1 - 2023

N2 - Introduction: The human whipworm, Trichuris trichiura, is a Clade I parasitic nematode estimated to infect 289.6 million people globally1. The narrow-spectrum anthelmintic oxantel is one of the most effective single-dose treatment against whipworms in humans and domestic animals. However, the molecular targets of oxantel in Trichuris species are still unknown. Here, we investigated the roles of a nicotinic acetylcholine receptor subunit from the ACR-16 group and characterized the first ion channels from the model pig whipworm Trichuris suis and murine whipworm Trichuris muris.Method: Xenopus laevis oocytes expressing the ACR-16-like subunit from either T. suis or T. muris were studied using the two-electrode voltage-clamp technique. Results: Both T. suis and T. muris ACR-16-like subunits gave rise to homomeric receptors gated by acetylcholine. The Tsu-ACR-16-like receptor had a higher affinity for ACh (EC50 = 14.5 ± 1.0 µM) than the T. muris one (EC50 = 31.1 ± 0.3 µM). Surprisingly, both receptors were strongly activated by oxantel, whereas nicotine acted as a poor agonist. Hence, we found that oxantel and ACh were equally potent on the T. suis (EC50 = 9.5 ± 1.1 µM) and T. muris (EC50 = 32.7 ± 0.3 µM) ACR-16-like receptors. Furthermore, the Tsu-ACR-16-like receptor was more responsive to pyrantel and less responsive to the toxic agonist epibatidine as compared to the Tmu-ACR-16-like receptor, showing the pharmacological difference between closely related species. Finally, the electrophysiological results of the Tsu-ACR-16-like receptor were confirmed in vivo by heterologous expression of the Tsu-ACR-16-like subunit in Caenorhabditis elegans conferring an increased sensitivity to oxantel.Conclusion: Altogether, these findings bring new insight into the understanding of the high sensitivity of whipworms to oxantel, and lay basis for the investigation of the O-AChR subtype in other Clade I parasites.

AB - Introduction: The human whipworm, Trichuris trichiura, is a Clade I parasitic nematode estimated to infect 289.6 million people globally1. The narrow-spectrum anthelmintic oxantel is one of the most effective single-dose treatment against whipworms in humans and domestic animals. However, the molecular targets of oxantel in Trichuris species are still unknown. Here, we investigated the roles of a nicotinic acetylcholine receptor subunit from the ACR-16 group and characterized the first ion channels from the model pig whipworm Trichuris suis and murine whipworm Trichuris muris.Method: Xenopus laevis oocytes expressing the ACR-16-like subunit from either T. suis or T. muris were studied using the two-electrode voltage-clamp technique. Results: Both T. suis and T. muris ACR-16-like subunits gave rise to homomeric receptors gated by acetylcholine. The Tsu-ACR-16-like receptor had a higher affinity for ACh (EC50 = 14.5 ± 1.0 µM) than the T. muris one (EC50 = 31.1 ± 0.3 µM). Surprisingly, both receptors were strongly activated by oxantel, whereas nicotine acted as a poor agonist. Hence, we found that oxantel and ACh were equally potent on the T. suis (EC50 = 9.5 ± 1.1 µM) and T. muris (EC50 = 32.7 ± 0.3 µM) ACR-16-like receptors. Furthermore, the Tsu-ACR-16-like receptor was more responsive to pyrantel and less responsive to the toxic agonist epibatidine as compared to the Tmu-ACR-16-like receptor, showing the pharmacological difference between closely related species. Finally, the electrophysiological results of the Tsu-ACR-16-like receptor were confirmed in vivo by heterologous expression of the Tsu-ACR-16-like subunit in Caenorhabditis elegans conferring an increased sensitivity to oxantel.Conclusion: Altogether, these findings bring new insight into the understanding of the high sensitivity of whipworms to oxantel, and lay basis for the investigation of the O-AChR subtype in other Clade I parasites.

M3 - Conference abstract for conference

T2 - Control of Human Disease Vectors, Pests and Parasites - Meeting the challenges of resistance and sustainability

Y2 - 18 September 2023 through 21 September 2023

ER -