Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity.
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-f...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-03-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC5388498?pdf=render |
| _version_ | 1819195468291244032 |
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| author | Laura Jeacock Nicola Baker Natalie Wiedemar Pascal Mäser David Horn |
| author_facet | Laura Jeacock Nicola Baker Natalie Wiedemar Pascal Mäser David Horn |
| author_sort | Laura Jeacock |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T02:13:14Z |
| format | Article |
| id | doaj.art-3a00db504e65484d9c721ae4a0b49749 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-23T02:13:14Z |
| publishDate | 2017-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-3a00db504e65484d9c721ae4a0b497492022-12-21T18:03:44ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-03-01133e100630710.1371/journal.ppat.1006307Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity.Laura JeacockNicola BakerNatalie WiedemarPascal MäserDavid HornAquaglyceroporins (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.http://europepmc.org/articles/PMC5388498?pdf=render |
| spellingShingle | Laura Jeacock Nicola Baker Natalie Wiedemar Pascal Mäser David Horn Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. PLoS Pathogens |
| title | Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. |
| title_full | Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. |
| title_fullStr | Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. |
| title_full_unstemmed | Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. |
| title_short | Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. |
| title_sort | aquaglyceroporin null trypanosomes display glycerol transport defects and respiratory inhibitor sensitivity |
| url | http://europepmc.org/articles/PMC5388498?pdf=render |
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