The African trypanosome (Trypanosoma brucei) diverged early from the eukaryotic lineage and is an important parasite of humans and their livestock. Many fundamental molecular and biochemical processes were first discovered in trypanosomes, some ‘unusual’, others broadly conserved. An excellent range of advanced experimental tools and resources make them highly tractable organisms.
Human African trypanosomiasis (sleeping sickness) and Animal African trypanosomiasis (nagana for example) exact a huge burden of disease. There are no vaccines, untreated sleeping sickness is typically fatal and current drugs display a range of undesirable features. We identified >50 genes linked to drug action and resistance, including a gene encoding a water channel that explains arsenic-based drug-resistance in patients from Sudan and the DRC. Current work in this area includes collaborative work with the Dundee Drug Discovery Unit. A deeper understanding of drug action and resistance should inform policy and practice and impact disease control efforts.
Genome-scale genetic screens can be extremely powerful and versatile for linking genes to cellular functions. We developed a high-throughput RNA Interference Target sequencing (RIT-seq) approach and initially used this approach to help prioritise drug targets. RIT-seq now opens up a whole range of opportunities in terms of decoding molecular mechanisms. We are currently tackling several phenotypes of interest, including monogenic expression and resistance to new drug candidates.
Monogenic expression is a fundamental gene-expression mechanism that is not understood in any system. Immune evasion in the malaria parasite and the African trypanosome and even our sense of smell depend upon it. In T. brucei, a single Variant Surface Glycoprotein (VSG) is expressed at a telomere. Antigenic variation involves VSG recombination or telomeric VSGs switching on and off. We seek to understand these processes through identification of the cis-acting elements and the trans-acting factors involved. In particular, we want to understand the molecular mechanisms underlying this classic example of monogenic expression.