Characterising the influence of parasite variation on visceral leishmaniasis.

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Visceral leishmaniasis, also called kala azar, is a neglected infectious disease that affects the world poorest in over 98 countries, resulting in 20,000 fatalities a year. Kala azar is caused by single-celled Leishmania parasites that are transferred by sand flies and migrate to internal organs such as the spleen or bone marrow. The disease is frequently fatal if untreated. Better treatments are essential to eliminate kala azar from poor communities. There is no vaccine to protect people in regions where sand flies carry the parasite. Drugs that are used to treat the disease can cause painful adverse effects, require hospitalisation and do not reliably kill all the parasites. Drug-resistant parasites have also evolved several times. Even when drugs do cure patients, kala azar parasites can persist in disfiguring skin lesions called post-kala azar dermal leishmaniasis (PKDL). It is important to cure PKDL, because the lesions contain live parasites, they are sources of new transmission by sand flies and may fuel new disease outbreaks. At present, we do not know why PKDL occurs, or how to stop it.Most cases of kala azar occur in Brazil, Ethiopia, India, Kenya, Somalia, South Sudan and Sudan. Different forms of kala azar and PKDL occur between continents and within countries. For example, PKDL is common in some regions of East Africa, but never occurs in other regions. African and Indian PKDL also takes different forms. This may be due to genetic differences between the people, or because the Leishmania parasites are different, so cause different types of disease. The role of parasite variation on disease variation is not well established. It is important to understand the differences between parasites because they may require different treatments, for example it is known that some anti-Leishmania drugs are effective in India, but not effective in Brazil. Investigating parasite variation may also help us to understand how parasites evade immune systems and persist for months or years as skin lesions. This project will study the influence of parasite genetic variation on kala azar and PKDL. It is known that East Africa contains the most genetically diverse Leishmania donovani ecotypes, so Africa is the best place to study this. We will work with a kala azar study in East Africa that is collecting detailed clinical and immune cell data from 40 patients in each of Sudan, Ethiopia, Kenya and Uganda (160 in all). Patient immune cells in blood will be taken before treatment, after treatment, and then months later when PKDL can occur. We will isolate the Leishmania parasites from each of the 160 patients when they are diagnosed and enrolled in the study. We will sequence the parasite genomes, and produce a detailed catalogue of all the genetic differences between them.Because every species carries their evolutionary history in their genes, we can use these genomes to describe current and historic parasite migration across East Africa, showing how ecotypes are distributed. We will then use genetic methods to determine whether difference between parasites cause differences in kala azar symptoms or cause PKDL. We will be able to provide some early warning of the evolution of drug resistant parasites in Sudan, Ethiopia, Kenya or Uganda. Leishmania parasites alter host immune systems to evade detection. Because we will have detailed immune cell data from each patient, we can also determine whether some parasites are more effective at evading the immune system. Finally, we will be able to determine if specific parasite genes help them evade the immune system, cause PKDL or allow them to resist drugs. This study will produce a better understanding of the parasites that cause kala azar and PKDL. This research may help us to design new drugs or new vaccines so we can eliminate the disease.