AbstractScabies has remained a worldwide problem for centuries, although its importance is frequently underestimated. It is a significant disease of children, especially in remote Aboriginal communities in northern Australia. Ivermectin has been identified as a potentially effective acaricide for mass treatment programs in scabies endemic communities, and is the treatment of choice for hyperinfested (crusted) scabies. Reports of ivermectin resistance in scabies mites raise concerns for the sustainability of such programs. It is therefore critical to define the molecular mechanisms of ivermectin resistance.
This study involved identification and characterisation of candidate genes associated with ivermectin resistance in scabies mites. Key outcomes included:
a) Identification and partial sequencing of nine ABC transporters from Sarcoptes scabiei var. hominis, five of which have been implicated in multidrug resistance in other organisms, including P-glycoprotein, previously associated with ivermectin resistance in parasitic nematodes.
b) Development of a quantitative reverse-transcriptase PCR assay to study the expression levels of candidate resistance genes in S. scabiei. Significantly, up-regulation of a delta-class glutathione-S-transferase and a multidrug resistance protein was associated with ivermectin exposure.
c) Characterisation of a novel ligand gated ion channel from S. scabiei var. hominis. The channel was shown to be modulated by pH and potentiated by ivermectin by functional expression in Xenopus laevis. Single strand conformational polymorphism analysis indicated that regions of this gene were highly polymorphic. This protein may act as the target site of ivermectin in scabies mites and therefore may be of considerable importance to the development of drug resistance.
These approaches have given us new insights into scabies mite biology and mechanisms for emerging ivermectin resistance. These may eventually assist in overcoming many of the current difficulties in monitoring treatment efficacy and allow the development of more sensitive tools for monitoring emerging resistance in the community.
|Date of Award||Mar 2007|
|Supervisor||Shelley Walton (Supervisor) & Deborah Holt (Supervisor)|