Assessing treatment with miltefosine as an intervention strategy for visceral leishmaniasis in Brazil

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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; it is caused by Leishmania infantum and transmitted by sandflies. Unfortunately the drugs available to treat VL have many limitations and new drugs, or new ways of using currently licensed drugs are desperately needed. One such drug is miltefosine, which has been used successfully to treat VL in India, but which was not so successful in a clinical trial in Brazil in 2006. Our recent research suggests that a specific section of the L. infantum genome (termed the MSL) is lost in some Brazilian strains of the parasite making them less susceptible to the drug miltefosine. The aim of our foundation project is to determine how prevalent the MSL is in the population of parasites that are found in Brazil. To do this we will validate a genetic diagnostic test using PCR, as well as sequence the genomes of L. chagasi parasites isolated from patients in the State of Piaui in Brazil. If the MSL is found to be present often, then a new clinical trial could be run, where leishmaniasis patients with parasites containing the MSL would be treated with miltefosine, whilst those leishmaniasis patients with parasites that do not contain the MSL would be treated using current drugs. We will genetically manipulate the MSL genes in Leishmania genes to find out why the MSL confers sensitivity to miltefosine. We shall also investigate why the MSL is lost in L. infantum, by testing if a natural product found in local Brazilian trees causes selection of parasites whilst in the sandfly vector. Overall, we expect the outcome from this study to be a greatly improved understanding of how the environment in which the parasite lives influences its susceptibility to drugs and the molecular mechanisms of drug resistance.