Abstract
BackgroundApproximately 200 million people worldwide harbour parasitic flatworm infections that cause schistosomiasis. A single drug—praziquantel (PZQ)—has served as the mainstay pharmacotherapy for schistosome infections since the 1980s. However, the relevant in vivo target(s) of praziquantel remain undefined.Methods and FindingsHere, we provide fresh perspective on the molecular basis of praziquantel efficacy in vivo consequent to the discovery of a remarkable action of PZQ on regeneration in a species of free-living flatworm (Dugesia japonica). Specifically, PZQ caused a robust (100% penetrance) and complete duplication of the entire anterior-posterior axis during flatworm regeneration to yield two-headed organisms with duplicated, integrated central nervous and organ systems. Exploiting this phenotype as a readout for proteins impacting praziquantel efficacy, we demonstrate that PZQ-evoked bipolarity was selectively ablated by in vivo RNAi of voltage-operated calcium channel (VOCC) β subunits, but not by knockdown of a VOCC α subunit. At higher doses of PZQ, knockdown of VOCC β subunits also conferred resistance to PZQ in lethality assays.ConclusionsThis study identifies a new biological activity of the antischistosomal drug praziquantel on regenerative polarity in a species of free-living flatworm. Ablation of the bipolar regenerative phenotype evoked by PZQ via in vivo RNAi of VOCC β subunits provides the first genetic evidence implicating a molecular target crucial for in vivo PZQ activity and supports the ‘VOCC hypothesis’ of PZQ efficacy. Further, in terms of regenerative biology and Ca2+ signaling, these data highlight a novel role for voltage-operated Ca2+ entry in regulating in vivo stem cell differentiation and regenerative patterning.
Highlights
Flatworms (‘platyhelminths’) comprise a diverse grouping of,25,000 species representing some of the simplest organisms that are triploblastic and bilaterally symmetric
Ablation of the bipolar regenerative phenotype evoked by PZQ via in vivo RNAi of voltage-operated calcium channel (VOCC) b subunits provides the first genetic evidence implicating a molecular target crucial for in vivo PZQ activity and supports the ‘VOCC hypothesis’ of PZQ efficacy
PZQ causes bipolar regeneration Figure 1A depicts a simple, manual screen focused on anteriorposterior (AP) regenerative polarity in the planarian Dugesia japonica
Summary
Flatworms (‘platyhelminths’) comprise a diverse grouping of ,25,000 species representing some of the simplest organisms that are triploblastic and bilaterally symmetric. The most clinically important of these is Schistosomiasis (Bilharzia) caused by infection with trematode flukes of the Schistosoma genus that infects ,200 million people worldwide [1,2]. As the mainstay of pharmacotherapy, the fact that the relevant in vivo targets of PZQ remain to be identified prevents rational design of the generation of antischistosomal chemotherapeutics and is clearly a precarious scenario relative to the potential emergence of drug resistance [3,4]. No single target has received unequivocal experimental support, and the relevant in vivo molecule(s)/pathway(s) targeted by PZQ remain elusive [2,5]. 200 million people worldwide harbour parasitic flatworm infections that cause schistosomiasis. The relevant in vivo target(s) of praziquantel remain undefined
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
