Grant: CIHR Fellowship

Cutaneous leishmaniasis (CL) is an infectious skin disease caused by Leishmania parasites and is transmitted by the bite of a sandfly. The skin lesion of CL begins as a small papule at the site of inoculation, usually at an exposed body part such as the face or extremities, which slowly grows and becomes ulcerated. Without treatment, the ulcer ultimately heals over 3 to 18 months and leaves a permanent disfiguring scar with psychosocial sequelae. Up to 10% of CL cases will progress, become chronic, and exhibit more severe clinical features. Unfortunately, there is no effective vaccine for prevention of CL and currently available therapeutic options are invasive, have toxic systemic side effects, and show varied efficacy. Although, CL is endemic in over 70 countries, including United States, and is diagnosed in up to one million new cases annually, this devastating disease is a World Health Organization top neglected tropical disease. Granzyme B (GzmB) is a protein that is aberrantly elevated in CL lesions and other inflammatory skin conditions. GzmB activity has been demonstrated to cleave important proteins in the skin, aggravating tissue damage, delayed wound healing, and scarring in human skin specimens and experimental models. Importantly, inhibition of GzmB have shown efficacy in impeding these disease phenotypes. In recent years, accumulating reports have linked GzmB expression and activity to disease severity measures of CL but GzmB's functional role is unexplored. Herein, we hypothesize that in CL lesions, GzmB contributes to inflammation, impaired wound healing, and scarring that can be averted by a GzmB inhibitor. To test this hypothesis, our 3-pronged approach will include lesional specimens from CL patients, a well-established experimental model to study GzmB function, and a GzmB inhibitor, Serpina3n. Together, the proposed study findings will provide key rationale to pursue GzmB as a novel therapeutic target for the treatment of CL.