University of Dundee

Professor David Horn

Antigenic variation, drug resistance and RNAi screens in trypanosomes
Position: 
Professor of Parasite Molecular Biology
Address: 
College of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 386286, int ext 86286
Email: 

Research

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.

Publications

  1. Graf FE., Ludin P, Wenzler T, Kaiser M, Brun R, Pyana PP, Büscher P, de Koning HP, Horn D, Mäser P. (2013) Aquaporin 2 mutations in Trypanosoma brucei gambiense field isolates correlate with decreased susceptibility to pentamidine and melarsoprol PLoS Neg. Trop. Dis. In press.
  2. Gould MK, Bachmaier S, Ali JAM, Alsford S, Tagoe DN, Munday JC, Schnaufer AC, Horn D, Boshart M, De Koning HP. (2013) Cyclic AMP effectors in African trypanosomes revealed by genome-scale RNAi library screening for resistance to the phosphodiesterase inhibitor Cpd A. Antimicrob. Agents Chemother. 57:4882-4893.
  3. Glover L, Alsford S & Horn D (2013) DNA break site at fragile subtelomeres determines probability and mechanism of antigenic variation in African trypanosomes. PLoS Pathogens. 9:e1003260.
  4. Horn D & Duraisingh MT. (2013) Antiparasitic Chemotherapy: From Genomes to Mechanisms. Annual Review of Pharmacology and Toxicology In press.
  5. Glover L, Hutchinson S, Alsford S, McCulloch R, Field MC & Horn D. (2013) Antigenic variation in African trypanosomes: the importance of chromosomal and nuclear context in VSG expression control. Cell. Microbiol. In press.
  6. Horn D. (2013) high-throughput decoding of drug targets and drug resistance mechanisms in African trypanosomes. Parasitology. In Press.
  7. Alsford S, Kelly JM, Baker N, & Horn D. (2013) Genetic dissection of drug resistance in trypanosomes. Parasitology 140:1478-1491.
  8. Alsford S, Field MC, and Horn D. (2013) Receptor mediated endocytosis for drug delivery in African Trypanosomes: fulfilling Paul Ehrlich’s vision of chemotherapy. Trends in Parasitol. 29:207-212.
  9. Baker N, de Koning HP, Mäser P, Horn D. (2013) Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story Trends in Parasitol. 29: 110-118.
  10. Alsford S & Horn D (2012) Cell-cycle-regulated control of VSG expression site silencing by histones and histone chaperones ASF1A and CAF-1b in Trypanosoma brucei. Nucleic Acids Res. 40:10150-60.
  11. 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.
  12. duBois K, Alsford S, Buisson J, Swiderski M, Bart J, Bastin P, Barry D, Navarro M, Horn D, Aitchison J, Rout M and Field M. (2012) Identification of a coiled-coil lamin-like protein in Trypanosoma brucei. PLOS Biology. 10:e1001287.
  13. Kelly J, Taylor M, Horn D, Loza E, Kalvinsh I and Björkling F. (2012) Histone deacetylase inhibitors with potent activity against the African trypanosome Trypanosoma brucei. Bioorganic & Medicinal Chemistry Letters. 22: 1886-90.
  14. Glover L and Horn D. (2012) Trypanosomal histone gH2A and the DNA damage response. Mol. Biochem. Parasitol. 183:78-83.
  15. 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.
  16. Alsford S, duBois K, Horn D and Field MC. (2012) Epigenetic mechanisms, nuclear architecture and control of gene expression in trypanosomes. Exp. Rev. Mol. Med. 14:e13.
  17. Field MC, Horn D, Alsford S, Koreny L & Rout MP. (2012) Telomeres, tethers and trypanosomes Nucleus. 3:1-9.
  18. Alsford S, Turner DJ., Obado SO, Sanchez-Flores A, Glover L, Berriman M, Hertz-Fowler C and Horn D. (2011) High throughput phenotyping using parallel sequencing of RNA interference targets in the African trypanosome. Genome Research. 21: 915-924.
  19. Alsford S and Horn D. (2011) Elongator Protein 3b Negatively Regulates Ribosomal DNA Transcription in African Trypanosomes. Mol. Cell. Biol. 31: 1822-1832.
  20. Baker N, Alsford S, and Horn D. (2011) Genome-wide RNAi screens in African trypanosomes identify the nifurtimox activator NTR and the eflornithine transporter AAT6. Mol. Biochem. Parasitol. 176: 55-57.
  21. Glover L, Jun J and Horn D. (2011) Microhomology mediated deletion and gene conversion in African trypanosomes. Nucleic Acids Res. 39: 1372-1380.
  22. Wang QP, Kawahara T and Horn D. (2010) Histone deacetylases play distinct roles in telomeric VSG expression site silencing in African trypanosomes. Mol. Microbiol. 5: 1237–1245.
  23. Alsford S, Kemp LE, Kawahara T and Horn D. (2010) RNA interference, growth and differentiation appear normal in African trypanosomes lacking Tudor staphylococcal nuclease. Mol. Biochem. Parasitol. 174:70-73.
  24. Horn D and McCulloch R. (2010) Molecular mechanisms underlying the control of antigenic variation in African trypanosomes Curr. Opin. Microbiol. 13: 700-705.
  25. Glover L and Horn D. (2009) Site-specific DNA double-strand breaks greatly increase stable transformation efficiency in Trypanosoma brucei. Mol. Biochem. Parasitol. 166: 194-197.
  26. McCulloch R and Horn D. (2009) What has DNA sequencing revealed about the VSG Expression Sites of African Trypanosomes? Trends. Parasitol. 25: 359-363.
  27. Alsford S, Horn D and Glover L. (2009) DNA breaks – driving antigenic variation in the African trypanosome. Genome Biol. 10: 223.
  28. Horn D. (2009) Antigenic variation: Extending the reach of telomeric silencing. Curr. Biol. 19: R496-498.
  29. Kawahara T, Siegel TN, Ingram AK, Alsford S, Cross GAM and Horn D. (2008) Two essential MYST-family proteins display distinct roles in histone H4K10 acetylation and telomeric silencing in trypanosomes. Mol. Microbiol. 69:1054-1068.
  30. Alsford S and Horn D. (2008) Single-locus targeting vectors for regulated transgene expression and RNAi in T. brucei. Mol. Biochem. Parasitol. 161: 76-79.
  31. Glover L, McCulloch R and Horn D. (2008) Sequence homology and microhomology dominate chromosomal double-strand break repair in African trypanosomes. Nucl. Acids Res. 36: 2608-2618.
  32. Wilkinson SR, Taylor MC, Horn D, Kelly JM and Cheeseman I. (2008) A mechanism for cross-resistance to nifurtimox and benznidazole in trypanosomes. Proc. Natl. Acad. Sci. USA. 105: 5022-5027.
  33. Siegel TN, Kawahara T, DeGrasse JA, Janzen CJ, Horn D and Cross GAM. (2008) Acetylation of histone H4K4 is cell-cycle regulated and mediated by HAT3 in Trypanosoma brucei Mol. Microbiol. 67: 762-771.
  34. Horn D. (2008) Codon usage suggests that translational selection has a major impact on protein expression in trypanosomatids. BMC Genomics. 9: 2.
  35. Field MC, Horn D and Carrington M. (2008) Analysis of small GTPase function in trypanosomes. Elsevier: Methods Enzymol. 438: 57-76.
  36. Horn D. (2008) Histone Deacetylases. Landes Bioscience. Drug targets in kinetoplastid parasites: Adv. Exp. Med. Biol. 625: 81-6.