Professor David Horn FRSE
African trypanosomes are parasitic protists which cause sleeping sickness or Human African Trypanosomiasis (HAT) and the livestock disease, nagana. They are masters of antigenic variation and immune evasion in the host bloodstream. One goal is to understand the molecular mechanisms underlying this process. DNA repair is required to replace the active Variant Surface Glycoprotein (VSG) gene with a new VSG and VSG expression is monoallelic (at a telomere) so our work in this area focuses on understanding mechanisms of DNA recombination and monotelomeric gene expression.
We also seek to understand drug action and resistance. We recently identified >50 genes linked to drug action. Suramin uptake was shown to be via receptor (ISG75)-mediated endocytosis while an aquaglyceroporin (AQP2) controls melarsoprol-pentamidine cross-resistance; AQP2 has now also been linked to clinical cases of melarsoprol resistance.
Our exploitation of genome sequence data is underpinned by technology development. In particular, we have developed an RNAi library screening method called RNA Interference Target sequencing or RIT-seq. Our research is supported by the Wellcome Trust and the Medical Research Council and DH is a Wellcome Trust Senior Investigator.
1. Glover L, Hutchinson S, Alsford S, Horn D. (2016) VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes. Proc. Natl Acad. Sci. USA.113:7225-30.
2. Baker N, Hamilton G, Wilkes J, Hutchinson S, Barrett MP, Horn D. (2015) Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency and drug-sensitivity in trypanosomes. Proc. Natl Acad. Sci. USA. 112:9112-9117.
3. Mony BM, MacGregor P, Ivens A, Rojas F, Cowton A, Wilson J, Horn D and Matthews KR (2014) Genome wide dissection of the quorum sensing signaling pathway in Trypanosoma brucei. Nature. 505:681-685.
4. Rudd SG, Glover L, Jozwiakowski SK, Horn D and Doherty AJ (2013) PPL2 translesion polymerase is essential for the completion of chromosomal DNA replication in the African trypanosome.Mol. Cell 52:554-565.
5. Baker N, Glover L, Munday JC, Aguinaga Andrés D, Barrett MP, de Koning HP, and Horn D.(2012) Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes.Proc. Natl Acad. Sci. USA. 109:10996–11001.
6. Alsford S, Eckert S, Baker N, Glover L, Sanchez-Flores A, Leung K, Turner DJ, Field MC, Berriman M and Horn D.(2012) High-throughput decoding of antitrypanosomal drug efficacy and resistance. Nature. 482: 232-236.
7. Alsford S, Turner DJ., Obado SO, Sanchez-Flores A, Glover L, Berriman M, Hertz-Fowler C and HornD. (2011) High throughput phenotyping using parallel sequencing of RNA interference targets in the African trypanosome. Genome Research. 21: 915-924.
8. Glover L, Jun J andHorn D. (2011) Microhomology mediated deletion and gene conversion in African trypanosomes. Nucleic Acids Res.39: 1372-1380.
9. Glover L, McCulloch R andHorn D. (2008) Sequence homology and microhomology dominate chromosomal double-strand break repair in African trypanosomes. Nucl. Acids Res. 36: 2608-2618.
10. Horn Dand Cross GAM. (1995) A developmentally regulated position effect at a telomeric locus in Trypanosoma brucei. Cell. 83: 555-561.