Grant: Project Grant

Leishmaniasis are complex spectrum of diseases that affect over 12 million people globally with an estimated 350 million people at risk of becoming infected. Depending on the species of Leishmania and host genetics, the disease manifestation ranges from small self-healing skin ulcers to large disfiguring scars and involvement of the liver, spleen and bone marrow that results in death. Despite this significant health and societal burden, there is currently no effective vaccine against the disease. Worse still, the existing treatments either cause major side effects or are only minimally effective. The lack of effective vaccine is mainly due to poor understanding of how a special type of immune cells, called memory cells work. Humans and animals that recover from infection remain immune for life, suggesting that memory cells able to protect against reinfection develop following recovery. My laboratory identified a conserved protein (expressed in all Leishmania species) that is critical for causing disease in mice. With the help of collaborators worldwide, we showed that this protein also induces strong immune response in human patients and dogs. These studies led to the development of first Leishmania reagent called tetramers, which is capable of identifying T cells that only respond to Leishmania at single cell level over the entire course of infection. It also allowed us to show that majority of the host immune response is directed against this protein. This unique reagent, which is now being used around the world, helped us to generate genetically engineered (transgenic) mice whose T cells only recognize this particular protein. We are now poised to use these animals to address fundamental questions regarding the factors that regulate the development, maintenance and loss of antigen-specific memory response in leishmaniasis. Understanding these factors is critical for development of effective vaccine and vaccination strategies against leishmaniasis.