Abstract
Schistosomiasis, caused by parasitic flatworms of the genus Schistosoma, is a neglected tropical disease affecting hundreds of millions globally. Praziquantel (PZQ), the only drug currently available for treatment and control, is largely ineffective against juvenile worms, and reports of PZQ resistance lend added urgency to the need for development of new therapeutics. Ion channels, which underlie electrical excitability in cells, are validated targets for many current anthelmintics. Transient receptor potential (TRP) channels are a large family of non-selective cation channels. TRP channels play key roles in sensory transduction and other critical functions, yet the properties of these channels have remained essentially unexplored in parasitic helminths. TRP channels fall into several (7–8) subfamilies, including TRPA and TRPV. Though schistosomes contain genes predicted to encode representatives of most of the TRP channel subfamilies, they do not appear to have genes for any TRPV channels. Nonetheless, we find that the TRPV1-selective activators capsaicin and resiniferatoxin (RTX) induce dramatic hyperactivity in adult worms; capsaicin also increases motility in schistosomula. SB 366719, a highly-selective TRPV1 antagonist, blocks the capsaicin-induced hyperactivity in adults. Mammalian TRPA1 is not activated by capsaicin, yet knockdown of the single predicted TRPA1-like gene (SmTRPA) in S. mansoni effectively abolishes capsaicin-induced responses in adult worms, suggesting that SmTRPA is required for capsaicin sensitivity in these parasites. Based on these results, we hypothesize that some schistosome TRP channels have novel pharmacological sensitivities that can be targeted to disrupt normal parasite neuromuscular function. These results also have implications for understanding the phylogeny of metazoan TRP channels and may help identify novel targets for new or repurposed therapeutics.
Highlights
Trematode flatworms of the genus Schistosoma cause schistosomiasis, a tropical parasitic disease that affects hundreds of millions globally [1,2], causing severe morbidity, compromised childhood development, and an estimated 280,000 deaths annually [3,4,5]
Suppressing expression of a different schistosome transient receptor potential (TRP) channel, TRPA1, which in mammals is not sensitive to capsaicin, almost completely eliminates this response. It appears that the pharmacology of schistosome TRP channels differs from that of host mammalian channels, a characteristic that might be exploitable for development of new antischistosomal drugs
A vanilloid compound that is an active ingredient in hot peppers, is a potent and selective activator/enhancer of TRPV1 [37]
Summary
Trematode flatworms of the genus Schistosoma cause schistosomiasis, a tropical parasitic disease that affects hundreds of millions globally [1,2], causing severe morbidity, compromised childhood development, and an estimated 280,000 deaths annually [3,4,5]. There is no vaccine, and treatment and control depend almost entirely on a single drug, praziquantel (PZQ) [6,7,8], which, though indispensable, has significant limitations, including reduced effectiveness against immature worms [9,10]. Ion channels are membrane proteins that form a gated pore, allowing ions to flow by diffusion down the electrochemical gradient established across cell membranes. They are vital for normal functioning of the neuromusculature, as well as for other cell types, and are validated and outstanding therapeutic targets [13,14]. One almost entirely unexplored group of schistosome (and other parasite) ion channels is the transient receptor potential (TRP) channel family [20]
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