Identification of novel anti-schistosomal therapies through studies of orthologous pathways during planarian regeneration

Abstract

The parasitic infection schistosomiasis afflicts over 200 million people and is clinically treated by a single drug - praziquantel (PZQ). Despite the fact that PZQ has served as a stalwart of anti-helminthic therapy for over three decades, it's molecular basis of action remains poorly understood. This roadblock prevents the rational design of alternative therapies and highlights the need for new approaches to study the parasitic flatworms that cause schistosomiasis. Towards this end, my thesis work has advanced the free living, non-parasitic planarian Dugesia japonica as an accessible laboratory model organism for studying flatworm gene function, identifying candidate druggable targets, and screening anti-parasitic lead compounds. The utility of this species derives in part from an unexpected phenology between regenerative outcomes in free living flatworms and lethality in parasitic species. These phenotypes were initially discovered through studies on the existing anti- schistosomal therapy, praziquantel, and I demonstrate that this phenology holds for a range of anti-schistosomal compounds with varying molecular targets and mechanisms of action. Capitalizing upon this phenology, experiments on the planarian D. japonica have yielded new insights into praziquantel's mechanism of action by linking the drug's efficacy to modulation of bioaminergic driven flatworm mobility. Expanding upon these initial findings in planarians, bioaminergic signaling was interrogated via pharmacological and genetic screens, revealing novel druggable targets (serotonin receptors) and lead compounds (ergot alkaloid derivatives) capable of subverting both planarian regeneration and parasite muscle function. Finally, given the predictive value of planarian regenerative outcomes in studying anti- parasitic therapies, I focused on understanding the regenerative patterning events that occur shortly after wounding. These studies demonstrate a crucial role for the CNS in determining regenerative outcomes, implicating a voltage operated Ca2+ channel isoform (Cav1B) and serotonin as key mediators of both "head" verses "tail" formation and flatworm muscle function. Collectively, the work presented in this thesis demonstrates the utility of a multi-species approach to resolve questions regarding the mechanism of action of the orphan drug praziquantel and to identify routes for novel anti-schistosomal drug development.