Leishmania virulence factors and host peptidases associated with visceral leishmaniasis

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Leishmaniasis is a severe disease of humans and one of the world's most neglected diseases, primarily affecting the poor in developing countries. 350 million people are at risk of contracting the disease and it has severe costs in both health and economic terms and drains resources that could be used to promote growth of developing nations. There is no effective vaccine against the disease and chemotherapy is the prime means for reducing the leishmaniasis burden. Visceral Leishmaniasis (VL) is the most severe form of leishmaniasis with 6,000 cases recorded in Brazil each year. Unfortunately the drugs available to treat VL have many limitations and new drugs are desperately needed. Our aim in this collaborative project is to characterise key biological processes of Leishmania chagasi, the parasite that causes VL in Brazil, and so identify factors that influence the outcome of disease. We have shown that peptidases, enzymes that digest proteins, and natural inhibitors that block peptidase function, are important in the infectivity and pathogenicity of the parasite. Our work will concentrate on 3 key areas of the biology of the parasite and its interaction with the host. Firstly, we will test if peptidases in the mammalian host are important for the pathogenesis of the disease. To do this we will use an animal model of infection using the L. chagasi parasite and mice. A key approach will be to genetically manipulate important Leishmania genes to find out what role the encoded proteins play in the parasite's infectivity and virulence and to determine whether they might be exploited as novel therapeutics. Secondly, we shall investigate the genome variation that occurs in different strains of Leishmania. We will sequence the genomes of L. chagasi parasites isolated from patients in the State of Piaui in Brazil with different clinical VL outcome and identify parasite genes that might influence the presentation of disease. We will integrate parasitological and immunological studies in animal models and humans and overall, we expect the outcome from this study to be a greatly improved understanding on the roles of these biological processes in Leishmania, and the molecular mechanisms of the processes themselves - which will be relevant to many areas of biology.