Scabies is a disease of worldwide importance caused by burrowing of the parasitic mite Sarcoptes scabiei into the lower stratum corneum of the epidermis. Infestation with S. scabiei causes an allergic type skin reaction with visible hypersensitivity lesions and pruritus, and results in significant morbidity primarily due to secondary infections with pathogenic bacteria. Until very recently there were no molecular studies on scabies because of the difficulty of obtaining mites. We have solved this problem by constructing a library of expressed S. scabiei sequences from mites obtained from skin shed into the bedding of patients with the severe form of the disease, crusted scabies.
Over 40,000 of these clones have been sequenced in collaboration with Deborah Holt, MSHR, Darwin and the Australian Genome Research Facility, providing a major resource for future studies. In searching for drug targets and vaccine candidates, we have chosen to focus our research on gut molecules and searched the cDNA database for homologues of the major allergens of house dust mites, the group 1 cysteine proteases and group 3 serine proteases. Unexpectedly, we identified multigene families of both S. scabiei group 1 and group 3 homologues. The remarkable feature of these is that they encode both active proteases as well as molecules which have the amino acids essential for catalysis mutated and thus cannot function as active proteases by any known mechanism. These had no counterparts in a library of house dust mite sequences.
Based on this data, we hypothesise that the genes for inactivated proteases have been amplified in the scabies mite genome to mediate novel host defence evasion strategies. We propose that they have evolved as an adaptation to parasitism of the epidermis, and may present unanticipated approaches to protective intervention. In collaboration with Ashley Buckle, James Whisstock and Rob Pike at Monash University, high resolution structures for two Inactivated Serine Protease Paralogues (SMIIPP-Ss) has been determined and binding properties studied.
Complement is one host defence system that has evolved to limit the capacity of pathogenic parasites to survive and multiply within the epidermis. We have discovered that SMIPP-Ss inhibit complement, presumably protecting the mite from complement-mediated gut damage. This is an essential requirement for the mite as its gut fills with epidermal and serum proteins during feeding. The mechanism of this is currently under study in collaboration with Ashley Buckle at Monash University, Melbourne and Anna Blom’s research group at Lund University in Malmö, Sweden.
ANIMATION: Skin crust with scabies mites
Movie courtesy of Charlene Willis (former PhD student in the Scabies Laboratory 2007)