Discussion

Despite decades of use and research the mode of action of the frontline anti-schistosomal drug praziquantel (PZQ) remains a mystery. However, recent advances in schistosome genomics provide us with new opportunities to investigate the action and impact of this drug. Here, we examine gene expression differences in immature (PZQ-insensitive) and adult (PZQ-sensitive) worms following treatment with PZQ in vivo. In combination with this approach we investigated the damage caused by PZQ through TEM and confocal microscopy, correlating transcriptional changes with physical damage. 778 genes were affected by PZQ in vivo, many of which were flatworm or Schistosoma specific. Of these, 327 genes showed differential expression between immature and adult worms. These genes were principally associated with worm structure (muscle tissue and tegument), fitting with damage to the basement membrane and muscle tissue observed through TEM and confocal microscopy. In adult worms, genes upregulated following treatment with PZQ were localised to identify tissue types most affected by drug exposure. Additional assays revealed cell death does not occur within the worm until around six hours after PZQ exposure. It is possible that structural disruption leads to host immune exposure which ultimately results in worm death.

Many studies on PZQ focus on drug effects and known genes/signaling pathways identified in other organisms, whilst here we have highlighted how many uncharacterised genes with no annotation or known homolog are also enriched by PZQ exposure. Together these data both provide a path to better understand the action of PZQ and also aid identification of potential novel drug targets, especially those involved in maintaining worm structure, where disruption could cause damage similar to that of PZQ.