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

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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

Fingerprint

Aquaglyceroporins
Respiratory Transport
Trypanosomiasis
Melarsoprol
Glycerol
Propyl Gallate
Trypanosoma brucei gambiense
Pentamidine
Osmoregulation
Poisons
Osmotic Pressure
Treatment Failure
Pharmaceutical Preparations
Parasites
Carbon

Keywords

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

Cite this

Jeacock, Laura ; Baker, Nicola ; Wiedemar, Natalie ; Mäser , Pascal ; Horn, David. / Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. In: PLoS Pathogens. 2017 ; Vol. 13, No. 3. pp. 1-16.
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Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. / Jeacock, Laura; Baker, Nicola; Wiedemar, Natalie; Mäser , Pascal; Horn, David (Lead / Corresponding author).

In: PLoS Pathogens, Vol. 13, No. 3, e1006307, 30.03.2017, p. 1-16.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity

AU - Jeacock, Laura

AU - Baker, Nicola

AU - Wiedemar, Natalie

AU - Mäser , Pascal

AU - Horn, David

N1 - This research was jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union (MR/K000500/1 to DH), by the Wellcome Trust (100320/Z/12/Z; Investigator Award to DH) and by the Swiss National Science Foundation (310030_156264). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2017/3/30

Y1 - 2017/3/30

N2 - 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 displayedonly 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.

AB - 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 displayedonly 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.

KW - Ascofuranone

KW - Gallate

KW - Glycolysis

KW - Melarsoprol

KW - Metabolism

KW - Mitochondrion

KW - Pentamidine

KW - Trypanosoma brucei

U2 - 10.1371/journal.ppat.1006307

DO - 10.1371/journal.ppat.1006307

M3 - Article

VL - 13

SP - 1

EP - 16

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 3

M1 - e1006307

ER -