Regulation of gene expression in Leishmania parasites: structure, function and post-transcriptional modification of RNA binding proteins

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 via sandfly bites. Only Leishmania parasites of certain lifecycle stage forms can infect and survive in humans. Major changes to the Leishmania parasite's appearance, metabolism and virulence occur during these transitions that enable them to survive. Gene expression in Leishmania relies almost exclusively upon regulation of messenger RNAs. 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 adaptation of these parasites enable them to survive in and infect humans. Such proteins are essential for the virulence and spread of the Leishmania parasite infection. The Leishmaniases are the second deadliest parasitic disease. Species of Leishmania threaten 350 million people worldwide on four continents. The World Health Organisation estimates 12 million people globally are currently infected and over 1 million new cases occur annually. No vaccine currently exists and available Leishmaniasis treatments are threatened by growing resistances and often overwhelmed by acute epidemics that are increasing in occurrence and severity. New treatments and vaccines are desperately needed and the UK government is committed to the World Health Organisation's recent call to further support Neglected Tropical Disease research. We have isolated specific RNA binding trans-regulatory proteins that are modified and regulated through arginine methylation. We have shown that levels of the methyltransferase enzyme responsible for this modification modulate Leishmania major infectivity and virulence. The project will focus on how arginine methylation modifies the 3D structure, interaction profile and function of target RNA binding proteins, and how this post-translational modification affects parasite infectivity and virulence. A molecular-level understanding of this epigenetic process will greatly advance our knowledge of post-transcriptional trans-regulation in Leishmania parasites.