Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity

Laura Jeacock, Nicola Baker, Natalie Wiedemar, Pascal Mäser , David Horn (Lead / Corresponding author)

Research output: Contribution to journalArticle

14 Citations (Scopus)
138 Downloads (Pure)

Abstract

Aquaglyceroporins (AQPs) transport water and glycerol and play important roles in drug-uptake in pathogenic trypanosomatids. For example, AQP2 in the human-infectious African trypanosome, Trypanosoma brucei gambiense, is responsible for melarsoprol and pentamidine-uptake, and melarsoprol treatment-failure has been found to be due to AQP2-defects in these parasites. To further probe the roles of these transporters, we assembled a T. b. brucei strain lacking all three AQP-genes. Triple-null aqp1-2-3 T. b. brucei displayed
only a very moderate growth defect in vitro, established infections in mice and recovered effectively from hypotonic-shock. The aqp1-2-3 trypanosomes did, however, display glycerol uptake and efflux defects. They failed to accumulate glycerol or to utilise glycerol as a carbon-source and displayed increased sensitivity to salicylhydroxamic acid (SHAM), octyl gallate or propyl gallate; these inhibitors of trypanosome alternative oxidase (TAO) can increase intracellular glycerol to toxic levels. Notably, disruption of AQP2 alone generated cells with glycerol transport defects. Consistent with these findings, AQP2-defective, melarsoprol-resistant clinical isolates were sensitive to the TAO inhibitors, SHAM, propyl gallate and ascofuranone, relative to melarsoprol-sensitive reference strains. We conclude that African trypanosome AQPs are dispensable for viability and osmoregulation but they make important contributions to drug-uptake, glycerol-transport and respiratory-inhibitor sensitivity. We also discuss how the AQP-dependent inverse sensitivity to melarsoprol and respiratory inhibitors described here might be exploited.
Original languageEnglish
Article numbere1006307
Pages (from-to)1-16
Number of pages16
JournalPLoS Pathogens
Volume13
Issue number3
DOIs
Publication statusPublished - 30 Mar 2017

Keywords

  • Ascofuranone
  • Gallate
  • Glycolysis
  • Melarsoprol
  • Metabolism
  • Mitochondrion
  • Pentamidine
  • Trypanosoma brucei

Fingerprint Dive into the research topics of 'Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity'. Together they form a unique fingerprint.

  • Projects

    Profiles

    Cite this