Grant: CIHR Fellowship

Cutaneous leishmaniasis (CL) is a skin infection that leads to blistering. Caused by protozoan Leishmania parasites, CL is transmitted by the bite of infected phlebotomine sandflies. This produces up to 200 lesions, typically on exposed parts of the body, such as the face, arms and legs, causing serious disability. In addition, lesions can leave permanent scars, which are often the cause of social prejudice. An estimated 1.3 million new cases are reported annually, with 30,000 of these resulting in death. Currently, there is no cure for CL. Granzyme B (GzmB) is a protein-degrading enzyme present in normal skin at minimal amounts. However, GzmB becomes elevated in skin that is cut, burnt, damaged by the sun or afflicted by various skin diseases. Here, GzmB prevents the skin from repairing itself and this leads to scarring. Previously, wounds in laboratory mice where GzmB was genetically knocked out showed improved healing and reduced visible signs of skin damage. In collaboration with viDA Therapeutics, the Granville Lab are developing novel inhibitors of GzmB that can be applied topically to the skin, showing emerging evidence of improved healing outcomes. Recent studies now indicate GzmB is elevated in the skin lesions of CL patients. Importantly, GzmB appears to be drastically more elevated in CL lesions than reported elsewhere in cuts, burns and other skin diseases. GzmB is therefore predicted to have an important role in the severity of CL. The aim of the current study is to investigate the contribution of GzmB to the development, severity and healing potential of CL lesions. We propose that the inhibition of GzmB, using topically applied drug formulations, will reduce lesion severity and improve visual appearance. CL is of major concern to the World Health Organization, and listed as one of the top 5 neglected diseases. The development of new therapeutic options for CL would have an enormous public health benefits.