AbstractScabies is a skin disease caused by the ectoparasitic mite Sarcoptes scabiei. It affectsmillions globally and is endemic in many populations. Current research in scabies isaimed at improving methods of diagnosis, elucidating determinants of hostpreference by scabies mites, and investigating host-parasite interactions, emergingresistance and novel therapeutic targets for disease control, among others.This study was designed to investigate the role of the S. scabiei aspartic protease,designated SsAP, in the life cycle of and as a determinant of host specificity by theparasite, and to characterise the physiological and physiochemical properties of thispotential drug target.
The expression and localisation studies conducted here revealed that SsAP is a strictacid protease present in the digestive tract and eggs of the scabies mite, with greatestexpression evident in the adult female mites. Recombinant SsAP from human mites,SsAP(Vh), was shown to digest haemoglobin, serum albumin, fibrinogen andfibronectin but not collagen III and laminin.In a comparative analysis of enzyme activity, it was observed that SsAP(Vh) canefficiently digest both human haemoglobin and human serum albumin, while SsAPfrom dog mites, SsAP(Vc), efficiently digests only human serum albumin. Thissuggests different dietary sources for these varieties of scabies mites and that theSsAP may determine the food preferences and host range of S. scabiei, as is the casein many other parasites.
Using a combinatorial library approach the primary specificity of SsAP(Vh) wasdetermined to be P1-Leu and P1’-Val. The extended specificity of SsAP(Vh) wasalso determined and may be exploited in the design of specific peptidomimeticinhibitors. An SsAP inhibitor which significantly impacted mite digestion and orreproduction would be a useful addition to currently used scabicidal drugs. Thiswould offer an alternative mode of therapy in the current conditions of emergingresistance. A new drug for scabies has the potential to have a significant positiveimpact on the health status of disadvantaged populations living in scabies endemiccommunities globally.
|Date of Award||2011|
|Supervisor||Deborah Holt (Supervisor) & Shelley Walton (Supervisor)|