Identifying and Characterising Developmental Regulators of Human Infectious Leishmania

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Species of Leishmania threaten 350 million people worldwide on four continents. The World Health Organisation estimates 12 million are currently infected and over 1 million new cases occur annually. No vaccine currently exists and available Leishmaniasis treatments are often overwhelmed by acute epidemics that are increasing in occurrence and severity. New treatments and vaccines are desperately needed and the UK government has committed to the World Health Organisation's recent call to further support Neglected Tropical Disease research. The single-cell Leishmania parasite transforms into many different forms during its lifecycle to adapt to very different hosts; moving from mammals to sandflies and back to mammals by sandfly bites. Only Leishmania parasites of certain lifecycle stage forms can infect and survive in humans. Major changes to the parasite's appearance, metabolism and virulence proteins occur during these transitions that enable them to survive. Leishmania gene expression relies almost exclusively upon mRNA regulation. In response to changes in the environment, specific parasite proteins bind mRNAs and target them for protein production to guide and promote adaptation. Proteins that control the changes these parasites go through enable them to adapt, survive in and infect humans. Such proteins are essential for the virulence and spread of the Leishmania parasite infection. By characterising such regulatory proteins and their downstream targets, we can find out what mechanisms the Leishmania parasites use to control their lifecycle changes. If we can isolate and stop control panel "Regulator" proteins, we can block the parasite from establishing an infection in humans. Significant findings would provide insight to Leishmaniasis research as well as diseases caused by related parasites, Chagas Disease and African Trypanosomiasis. Leishmania proteins are different from human proteins; therefore we can exploit these differences to target Leishmania-specific developmental regulators, block their function and block the parasites' ability to invade. Unfortunately, no Leishmania regulator proteins have yet been identified. I propose to find regulators of Leishmania spp. lifecycle changes, identify how they function, and test whether any are essential for parasite survival. Essential Regulators could serve as potential drug targets to block Leishmania parasite infection.