Defining the molecular determinants required for Leishmania life cycle progression and virulence

Leishmania parasites cause a neglected disease on the WHO priority list.

During their life cycle, these single-celled parasites must migrate through the sandfly (promastigotes), pre-adapt for mammalian infectivity (metacyclic promastigotes) and proliferate inside macrophages (amastigotes) while withstanding host immune defences.

Adaptation to these radically different environments involves many changes, including metabolic and cell structure specialisations, ensuring survival and transmission. However, current understanding of these processes is disjointed and biased towards predicted/expected pathways.

Half of Leishmania’s protein-coding genes, including most unique to Leishmania, have no known or predicted function, (the “dark genome”), leaving potentially exploitable parasite biochemistry untapped in the search for new therapeutics. We aim to identify all major parasite pathogenicity factors.

We will determine a) the subcellular localisation of all proteins with poorly predicted function (~50% of the genome) and b) the fitness cost of gene deletion in each life cycle stage (100% of the genome).

Integrative analysis of this deep dataset will identify key pathways in 1) organelle adaptation for an intracellular parasitic lifestyle and 2) host interaction, which we will then functionally dissect.

This will identify virulence factors on a genome scale, determine the most important pathways required for parasitism and illuminate the ‘dark genome’.