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The calcium-gated potassium channel SLO-1 in  Caenorhabditis elegans  was recently identified as key component for action of emodepside, a new anthelmintic drug with broad spectrum activity. In this study we identified orthologues of  slo-1  in  Ancylostoma caninum ,  Cooperia oncophora , and  Haemonchus contortus , all important parasitic nematodes in veterinary medicine. Furthermore, functional analyses of these  slo-1  orthologues were performed using heterologous expression in  C. elegans . We expressed  A. caninum  and  C. oncophora slo-1  in the emodepside-resistant genetic background of the  slo-1  loss-of-function mutant NM1968  slo-1(js379) . Transformants expressing  A. caninum slo-1  from  C. elegans slo-1  promoter were highly susceptible (compared to the fully emodepside-resistant  slo-1(js379) ) and showed no significant difference in their emodepside susceptibility compared to wild-type  C. elegans  (p = 0.831). Therefore, the SLO-1 channels of  A. caninum  and  C. elegans  appear to be completely functionally interchangeable in terms of emodepside sensitivity. Furthermore, we tested the ability of the 5′ flanking regions of  A. caninum  and  C. oncophora slo-1  to drive expression of SLO-1 in  C. elegans  and confirmed functionality of the putative promoters in this heterologous system. For all transgenic lines tested, expression of either native  C. elegans slo-1  or the parasite-derived orthologue rescued emodepside sensitivity in  slo-1(js379)  and the locomotor phenotype of increased reversal frequency confirming the reconstitution of SLO-1 function in the locomotor circuits. A potent mammalian SLO-1 channel inhibitor, penitrem A, showed emodepside antagonising effects in  A. caninum  and  C. elegans . The study combined the investigation of new anthelmintic targets from parasitic nematodes and experimental use of the respective target genes in  C. elegans , therefore closing the gap between research approaches using model nematodes and those using target organisms. Considering the still scarcely advanced techniques for genetic engineering of parasitic nematodes, the presented method provides an excellent opportunity for examining the pharmacofunction of anthelmintic targets derived from parasitic nematodes.

plos pathogens

SLO-1-Channels of Parasitic Nematodes Reconstitute Locomotor Behaviour and Emodepside Sensitivity in Caenorhabditis elegans slo-1 Loss of Function Mutants