Abstract
In the absence of efficient alternative strategies, the control of parasitic nematodes, impacting human and animal health, mainly relies on the use of broad-spectrum anthelmintic compounds. Unfortunately, most of these drugs have a limited single-dose efficacy against infections caused by the whipworm, Trichuris. These infections are of both human and veterinary importance. However, in contrast to a wide range of parasitic nematode species, the narrow-spectrum anthelmintic oxantel has a high efficacy on Trichuris spp. Despite this knowledge, the molecular target(s) of oxantel within Trichuris is still unknown. In the distantly related pig roundworm, Ascaris suum, oxantel has a small, but significant effect on the recombinant homomeric Nicotine-sensitive ionotropic acetylcholine receptor (N-AChR) made up of five ACR-16 subunits. Therefore, we hypothesized that in whipworms, a putative homolog of an ACR-16 subunit, can form a functional oxantel-sensitive receptor. Using the pig whipworm T. suis as a model, we identified and cloned a novel ACR-16-like subunit and successfully expressed the corresponding homomeric channel in Xenopus laevis oocytes. Electrophysiological experiments revealed this receptor to have distinctive pharmacological properties with oxantel acting as a full agonist, hence we refer to the receptor as an O-AChR subtype. Pyrantel activated this novel O-AChR subtype moderately, whereas classic nicotinic agonists surprisingly resulted in only minor responses. We observed that the expression of the ACR-16-like subunit in the free-living nematode Caenorhabditis elegans conferred an increased sensitivity to oxantel of recombinant worms. We demonstrated that the novel Tsu-ACR-16-like receptor is indeed a target for oxantel, although other receptors may be involved. These finding brings new insight into the understanding of the high sensitivity of whipworms to oxantel, and highlights the importance of the discovery of additional distinct receptor subunit types within Trichuris that can be used as screening tools to evaluate the effect of new synthetic or natural anthelmintic compounds.
Highlights
The human whipworm, Trichuris trichiura, is a Clade I parasitic nematode [1] and one of the Soil Transmitted Helminths (STHs) that is estimated to infect 289.6 million people globally, primarily those living in the tropics and subtropics [2]
The human whipworm, Trichuris trichiura, is an intestinal parasitic nematode infecting approximately 289.6 million people globally, primarily children living in developing countries
Whipworm infections are notoriously difficult to control with most available anthelmintics, including those commonly used in mass drug administration programs
Summary
The human whipworm, Trichuris trichiura, is a Clade I parasitic nematode [1] and one of the Soil Transmitted Helminths (STHs) that is estimated to infect 289.6 million people globally, primarily those living in the tropics and subtropics [2]. Clinical trials reported oxantel to be effective against T. trichiura infections [19, 20] and recent studies show that oxantel is superior to single-dose albendazole and mebendazole [21, 22], which are currently recommended by the WHO for the control of STHs [23]. Cholinergic agonists [16] exert their effect by paralyzing the worms, which are subsequently killed or expelled from the host [24]. This effect is mediated by nicotinic acetylcholine receptors (nAChRs) [24] that are either heteromeric or homomeric five-subunit ligand-gated ion channels expressed in neuronal, muscle and non-neuronal cell membranes [25, 26]. The N-AChR subtypes from the model nematode Caenorhabditis elegans and the distantly related pig parasite A. suum are
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