Increased transcription of Glutathione S-transferases in acaricide exposed scabies mites

Abstract

BackgroundRecent evidence suggests that Sarcoptes scabiei var. hominis mites collected from scabies endemic communities in northern Australia show increasing tolerance to 5% permethrin and oral ivermectin. Previous findings have implicated detoxification pathways in developing resistance to these acaricides. We investigated the contribution of Glutathione S-transferase (GST) enzymes to permethrin and ivermectin tolerance in scabies mites using biochemical and molecular approaches.ResultsIncreased in vitro survival following permethrin exposure was observed in S. scabiei var. hominis compared to acaricide naïve mites (p < 0.0001). The addition of the GST inhibitor diethyl maleate restored in vitro permethrin susceptibility, confirming GST involvement in permethrin detoxification. Assay of GST enzymatic activity in mites demonstrated that S. scabiei var. hominis mites showed a two-fold increase in activity compared to naïve mites (p < 0.0001). Increased transcription of three different GST molecules was observed in permethrin resistant S. scabiei var. canis- mu 1 (p < 0.0001), delta 1 (p < 0.001), and delta 3 (p < 0.0001). mRNA levels of GST mu 1, delta 3 and P-glycoprotein also significantly increased in S. scabiei var. hominis mites collected from a recurrent crusted scabies patient over the course of ivermectin treatment.ConclusionsThese findings provide further support for the hypothesis that increased drug metabolism and efflux mediate permethrin and ivermectin resistance in scabies mites and highlight the threat of emerging acaricide resistance to the treatment of scabies worldwide. This is one of the first attempts to define specific genes involved in GST mediated acaricide resistance at the transcriptional level, and the first application of such studies to S. scabiei, a historically challenging ectoparasite.

Acaricidal Activity of Eugenol Based Compounds against Scabies Mites

“…However, as it was not possible to perform repeat experiments with the resistant mites, these results should be interpreted with some caution. Higher levels of glutathione-S-transferase (GST) enzymes and upregulation of GST transcription in resistant mites compared to sensitive mites has been detected, and indicative of a metabolic basis for permethrin resistance in this mite colony [48]. Whether a similar pattern of resistance observed in these studies with the compounds tested is mediated by the same metabolic detoxification by GSTs as previously observed in permethrin resistant mites will need further investigation.…”

Gene silencing by RNA interference in the house dust mite, Dermatophagoides pteronyssinus

“…Such experiments might involve assessing mite survival when exposed to acaricides following RNAi, given the role that GSTs are known to play in acaricide resistance within the Acari [36e38]. In addition, translation level silencing of DpGST-mu1 could be ascertained by means of a fluorescence-based GST enzyme assay, whereby the fluorescence emitted as a result of the conjugation of reduced glutathione to a substrate such as monochlorobimane indicates GST activity [18,36]. However, the caveat would be that the remaining GSTs of different classes could account for residual GST activity through functional redundancy in mites following successful RNAi-mediated silencing of the DpGST-mu1 gene.…”

Impact of scabies in resource-poor communities

“…As some of these trials were not controlled, and methods were not standardized, the results should be interpreted with care. Resistance may develop after repeated and prolonged treatment with oral ivermectin and topical compounds [80][81][82][83].…”