Understanding differences in clinical presentations of cutaneous leishmaniasis in an endemic disease focus

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Leishmaniasis is one of the most important neglected tropical diseases: a group of diseases united by the fact that they impact the poorest communities and attract little political interest and less funding for control or basic research than other diseases. Transmitted by sandflies, leishmaniasis is a parasitic disease that affects an estimated 12 million people in 98 countries, causing disfiguring infections of the skin and other tissues, and tens of thousands of deaths. A striking feature of leishmaniasis is that diverse forms of the disease are caused by a single group of parasites. Visceral leishmaniasis (VL) occurs where parasites migrate and multiply in organs such as the liver and spleen. VL is usually fatal if not treated, as patients become immunocompromised and highly susceptible to other diseases. Cutaneous leishmaniasis (CL) is restricted to the skin and superficial tissues and can present in three different forms: localised CL (LCL) causes damage, such as small ulcers, only at the site of the insect bite; while other infections can be more widespread (diffuse CL; DCL) or when parasites invade and destroy mucosal tissue of the nose, lips or palate, leading to severe disfigurement (mucosal CL; MCL). There is a great variety in the severity of CL, with some infections healing spontaneously (usually LCL), while others persist and form large wounds. Healed lesions invariably result in scarring, which in some societies leads to severe social stigma and so has a profound impact on the lives of patients. These different forms of disease (known as clinical presentations) are associated with different species but there is substantial variation within species and it is poorly understood why Leishmania parasites cause different forms of disease. We propose to study CL in Ethiopia, where the disease is an important health problem. We will work in an area of North West Ethiopia, where Leishmania aethiopica is causing an increasing incidence of localised CL, diffuse CL and mucosal CL. Since the diseases occur in the same region and in the same human and vector populations, this focus is a unique place to unravel the biological basis of the different clinical presentation of CL. We will generate whole-genome data for parasites from each of the different presentations, and also quantify genome-wide host gene expression and the immune response to Leishmania infection in both the lesions and blood of patients with each form of CL. In this way we will identify the genes and types of immunity involved in particular types of CL. We have developed a non-invasive, painless way to sample CL-affected skin that allows us to take samples in the hard-to-reach communities most affected by the disease. The data from the clinical database will be used to explore if any clinical and epidemiological factors associated with the different presentations of CL in our cohort, but will also be included in the statistical analysis of the parasite and host data to identify and unravel associations with the different presentations. This study will elucidate the pathogenesis of CL, which is essential for the development of new strategies to prevent and treat leishmaniasis - both vaccines and better diagnostic tests. The project will also enhance capacity for biomedical research in Ethiopia and establish a framework for future research in this setting.