Regulating the trans-regulators: Investigating the PRMT7 molecular pathway as an epigenetic regulator of Leishmania spp. virulence

点击翻译按钮获取中文摘要

Species of Leishmania threaten 350 million people worldwide on four continents. The Leishmaniases are the second deadliest parasitic disease and all pathologies of this diverse disease are present in Brazil. 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 and Brazilian governments are 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 Leishmania parasite's appearance, metabolism and virulence occur during these transitions that enable them to survive. Gene expression in Leishmania 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 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. We have recently isolated a major control panel "Regulator" protein, PRMT7, which controls Leishmania parasite virulence in mammalian infections. Very few Leishmania regulator proteins have yet been identified and this finding represents a major leap forward to isolate and examine this regulatory pathway and block parasite virulence. To study the PRMT7 regulation pathway and identify the way this protein functions, we have assembled a team of experts in Leishmania parasite PRMT proteins, RNA regulators and protein interactions. We believe insight into this pathway will enable us to block the parasite from establishing human infections. We have identified some downstream target proteins of PRMT7 and now seek to determine if they are regulated by PRMT7 and whether they participate in Leishmania parasite virulence. Leishmania proteins are different from human proteins; therefore we can use these differences to target Leishmania- specific virulence factors, block their function and block Leishmaniasis from developing. Significant findings will provide insight to Leishmaniasis research as well as diseases caused by related parasites, Chagas Disease and African Trypanosomiasis.We propose to find more regulators of Leishmania spp. virulence using the PRMT7 virulence pathway. We will identify how these regulators function, and test whether any are essential for parasite survival. Essential Regulators could serve as potential drug targets to block Leishmania parasite infection.The novelty and importance of our project is four fold:1. PRMT7 is the only Protein aRginine Methyl Transferase enzyme that has been characterised in Leishmania spp. parasites thus far and it appears to block virulence (Ferreira et al., 2014). 2. Methylation as a protein modification is uncharacterised in Leishmania spp. parasites. 3. Regulatory RNA binding proteins (RBPs) that are important in parasite lifecycle differentiation, human infectivity and virulence are largely unknown in Leishmania spp.4. The 3-dimensional molecular structures of RBPs and mRNA:protein complexes are largely unknown in all parasites and are absent in Leishmania spp.