Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis
Benzimidazole-2-carbamates (BZ, e.g., albendazole; ALB), which bind β-tubulin to disrupt microtubule polymerization, are one of two primary compound classes used to treat giardiasis. In most parasitic nematodes and fungi, BZ-resistance is caused by β-tubulin mutations and its molecular mode of actio...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221132072300012X |
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| author | Qiao Su Louise Baker Samantha Emery Balu Balan Brendan Ansell Swapnil Tichkule Ivo Mueller Staffan G. Svärd Aaron Jex |
| author_facet | Qiao Su Louise Baker Samantha Emery Balu Balan Brendan Ansell Swapnil Tichkule Ivo Mueller Staffan G. Svärd Aaron Jex |
| author_sort | Qiao Su |
| collection | DOAJ |
| description | Benzimidazole-2-carbamates (BZ, e.g., albendazole; ALB), which bind β-tubulin to disrupt microtubule polymerization, are one of two primary compound classes used to treat giardiasis. In most parasitic nematodes and fungi, BZ-resistance is caused by β-tubulin mutations and its molecular mode of action (MOA) is well studied. In contrast, in Giardia duodenalis BZ MOA or resistance is less well understood, may involve target-specific and broader impacts including cellular damage and oxidative stress, and its underlying cause is not clearly determined. Previously, we identified acquisition of a single nucleotide polymorphism, E198K, in β-tubulin in ALB-resistant (ALB-R) G. duodenalis WB-1B relative to ALB-sensitive (ALB-S) parental controls. E198K is linked to BZ-resistance in fungi and its allelic frequency correlated with the magnitude of BZ-resistance in G. duodenalis WB-1B. Here, we undertook detailed transcriptomic comparisons of these ALB-S and ALB-R G. duodenalis WB-1B cultures. The primary transcriptional changes with ALB-R in G. duodenalis WB-1B indicated increased protein degradation and turnover, and up-regulation of tubulin, and related genes, associated with the adhesive disc and basal bodies. These findings are consistent with previous observations noting focused disintegration of the disc and associated structures in Giardia duodenalis upon ALB exposure. We also saw transcriptional changes with ALB-R in G. duodenalis WB-1B consistent with prior observations of a shift from glycolysis to arginine metabolism for ATP production and possible changes to aspects of the vesicular trafficking system that require further investigation. Finally, we saw mixed transcriptional changes associated with DNA repair and oxidative stress responses in the G. duodenalis WB-1B line. These changes may be indicative of a role for H2O2 degradation in ALB-R, as has been observed in other G. duodenalis cell cultures. However, they were below the transcriptional fold-change threshold (log2FC > 1) typically employed in transcriptomic analyses and appear to be contradicted in ALB-R G. duodenalis WB-1B by down-regulation of the NAD scavenging and conversion pathways required to support these stress pathways and up-regulation of many highly oxidation sensitive iron-sulphur (FeS) cluster based metabolic enzymes. |
| first_indexed | 2024-03-12T21:39:21Z |
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| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-03-12T21:39:21Z |
| publishDate | 2023-08-01 |
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| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-4dc27df364234738957f70e47311917c2023-07-27T05:55:47ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072023-08-0122919Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalisQiao Su0Louise Baker1Samantha Emery2Balu Balan3Brendan Ansell4Swapnil Tichkule5Ivo Mueller6Staffan G. Svärd7Aaron Jex8Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, AustraliaPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, AustraliaPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, AustraliaPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, AustraliaPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, AustraliaPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, AustraliaPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; Unité Malaria: Parasites et Hôtes, Département Parasites et Insectes Vecteurs, Institut Pasteur, F-75015, Paris, FranceDepartment of Cell and Molecular Biology, BMC, Uppsala University, Uppsala, SwedenPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; Corresponding author. Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.Benzimidazole-2-carbamates (BZ, e.g., albendazole; ALB), which bind β-tubulin to disrupt microtubule polymerization, are one of two primary compound classes used to treat giardiasis. In most parasitic nematodes and fungi, BZ-resistance is caused by β-tubulin mutations and its molecular mode of action (MOA) is well studied. In contrast, in Giardia duodenalis BZ MOA or resistance is less well understood, may involve target-specific and broader impacts including cellular damage and oxidative stress, and its underlying cause is not clearly determined. Previously, we identified acquisition of a single nucleotide polymorphism, E198K, in β-tubulin in ALB-resistant (ALB-R) G. duodenalis WB-1B relative to ALB-sensitive (ALB-S) parental controls. E198K is linked to BZ-resistance in fungi and its allelic frequency correlated with the magnitude of BZ-resistance in G. duodenalis WB-1B. Here, we undertook detailed transcriptomic comparisons of these ALB-S and ALB-R G. duodenalis WB-1B cultures. The primary transcriptional changes with ALB-R in G. duodenalis WB-1B indicated increased protein degradation and turnover, and up-regulation of tubulin, and related genes, associated with the adhesive disc and basal bodies. These findings are consistent with previous observations noting focused disintegration of the disc and associated structures in Giardia duodenalis upon ALB exposure. We also saw transcriptional changes with ALB-R in G. duodenalis WB-1B consistent with prior observations of a shift from glycolysis to arginine metabolism for ATP production and possible changes to aspects of the vesicular trafficking system that require further investigation. Finally, we saw mixed transcriptional changes associated with DNA repair and oxidative stress responses in the G. duodenalis WB-1B line. These changes may be indicative of a role for H2O2 degradation in ALB-R, as has been observed in other G. duodenalis cell cultures. However, they were below the transcriptional fold-change threshold (log2FC > 1) typically employed in transcriptomic analyses and appear to be contradicted in ALB-R G. duodenalis WB-1B by down-regulation of the NAD scavenging and conversion pathways required to support these stress pathways and up-regulation of many highly oxidation sensitive iron-sulphur (FeS) cluster based metabolic enzymes.http://www.sciencedirect.com/science/article/pii/S221132072300012XGiardia duodenalisAlbendazoleDrug-resistance |
| spellingShingle | Qiao Su Louise Baker Samantha Emery Balu Balan Brendan Ansell Swapnil Tichkule Ivo Mueller Staffan G. Svärd Aaron Jex Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis International Journal for Parasitology: Drugs and Drug Resistance Giardia duodenalis Albendazole Drug-resistance |
| title | Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis |
| title_full | Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis |
| title_fullStr | Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis |
| title_full_unstemmed | Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis |
| title_short | Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis |
| title_sort | transcriptomic analysis of albendazole resistance in human diarrheal parasite giardia duodenalis |
| topic | Giardia duodenalis Albendazole Drug-resistance |
| url | http://www.sciencedirect.com/science/article/pii/S221132072300012X |
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