Abstract
ABSTRACTAnthelmintic drugs are used to treat parasitic roundworm and flatworm infections in humans and other animals.Caenorhabditis elegansis an established model to investigate anthelmintics used to treat roundworms. In this study, we useC. elegansto examine the mode of action and the mechanisms of resistance against the flatworm anthelmintic drug praziquantel (PZQ), used to treat trematode and cestode infections. We found that PZQ inhibited development and that this developmental delay varies by genetic background. Interestingly, both enantiomers of PZQ are equally effective againstC. elegans, but only the left-handed PZQ (S-PZQ) is effective against schistosome infections. We conducted a genome-wide association mapping with 74 wildC. elegansstrains to identify a region on chromosome IV that is correlated with differential PZQ susceptibility. Five candidate genes in this region:cct-8, znf-782, Y104H12D.4, Y104H12D.2, andcox-18, might underlie this variation. The genecct-8, a subunit of the protein folding complex TRiC, has variation that causes a putative protein coding change (G226V), which is correlated with reduced developmental delay. Gene expression analysis suggests that this variant correlates with slightly increased expression of bothcct-8andhsp-70. Acute exposure to PZQ caused increased expression ofhsp-70, indicating that altered TRiC function might be involved in PZQ responses. To test if this variant affects development upon exposure to PZQ, we used CRISPR-Cas9 genome editing to introduce the V226 allele into the N2 genetic background (G226) and the G226 allele into the JU775 genetic background (V226). These experiments revealed that this variant was not sufficient to explain the effects of PZQ on development. Nevertheless, this study shows thatC. eleganscan be used to study responses to PZQ to identify mode of action and resistance mechanisms. Additionally, we show that the TRiC complex requires further evaluation for PZQ responses inC. elegans.
Publisher
Cold Spring Harbor Laboratory