Kinome-wide functional analysis of Leishmania growth and differentiation (360G-Wellcome-200807_Z_16_Z)

Leishmania species are trypanosomatid parasitic protozoa that are the causative agents of a spectrum of diseases, the leishmaniases. Whilst significant progress has been made in understanding the unique cell biology of Leishmania and its interaction with the mammalian host, little is known about the signalling pathways that regulate key events in the parasites’ life cycle and which protein kinases are essential and therefore potentially amenable to chemotherapeutic modulation. To address this we will carry out gain-of-function and loss-of-function genetic screens in Leishmania mexicana to identify protein kinases involved in signalling pathways regulating parasite differentiation during transition between animal and sandfly hosts. We will also identify those protein kinases essential for proliferation and survival of Leishmania once an infection is established in the two hosts. This will be possible because of recent development in genetic manipulation of Leishmania, including CRISPR-Cas9 genome engineering, tetracycline inducible over-expression and the use of rapamycin induced diCre recombinase to study the function of essential genes. The expected output of the project will be novel insights into protein kinase function in Leishmania and a holistic overview of cell signalling pathways that will integrate into ongoing "omics" analyses within the Leishmania community.