'Death and Axes': Unexpected Ca2+ Entry Phenologs Predict New Anti-schistosomal Agents

Schistosomiasis is a parasitic flatworm disease that infects 200 million people worldwide. The drug praziquantel (PZQ) is the mainstay therapy but the target of this drug remains ambiguous. While PZQ paralyses and kills parasitic schistosomes, in free-living planarians PZQ caused an unusual axis duplication during regeneration to yield two-headed animals. Here, we show that PZQ activation of a neuronal Ca2+ channel modulates opposing dopaminergic and serotonergic pathways to regulate head' structure formation. Surprisingly, compounds with efficacy for either bioaminergic network in planarians also displayed antischistosomal activity, and reciprocally, agents first identified as antischistocidal compounds caused bipolar regeneration in the planarian bioassay. These divergent outcomes (death versus axis duplication) result from the same Ca2+ entry mechanism, and comprise unexpected Ca2+ phenologs with meaningful predictive value. Surprisingly, basic research into axis patterning mechanisms provides an unexpected route for discovering novel antischistosomal agents. Author Summary Schistosomiasis (Bilharzia) is one of the most burdensome parasitic worm infections, encumbering third world economies with an annual loss of several million disability-adjusted life years. The key treatment for schistosome infections is the drug praziquantel but the mechanism of action of this drug remains controversial hampering targeted development of next generation antischistosomal agents. Here we provide fresh insight into the signaling pathways engaged by PZQ, by resolving commonalities in the action of PZQ with the process of regenerative signaling in free-living planarian flatworms. A similar calcium-dependent network is engaged in both model systems, but with divergent phenotypic outcomes. This relationship provides predictive insight such that basic research on signaling pathways involved in tissue regeneration reveals novel drug leads for schistosomiasis, and reciprocally schistosomal drug screens reveal targets involved in regenerative signaling. We believe this phenology will be helpful for uncovering new antischistosomal drug targets by exploiting broader vulnerabilities within the PZQ interactome.