Differential expression of β-tubulin isotypes in different life stages of Parascaris spp after exposure to thiabendazole.
Abstract: Anthelmintic resistance (AR) to macrocyclic lactones (ML) has been described in Parascaris of horses world-wide. In contrast, benzimidazoles (BZ) are still effective, although reduced efficacy to this drug class was recently reported. The mode of action of BZ is binding to β-tubulin, which prevents polymerisation of microtubules. In this study, β-tubulin gene expression of isotypes 1 and 2 was investigated at seven time points (0, 6, 24, 72, 96 and 120 h) during embryogenesis and in adult worms. In addition, an in ovo larval developmental test was developed to study β-tubulin gene expression of both isotypes in parasacaris eggs after exposure to different concentrations of thiabendazole (TBZ) for five days at 25 °C. A strong pattern of differential expression of β-tubulin and isotype 1 was observed in all stages, while isotype 2 expression was mainly found at an early phase of the embryogenesis. For isotype 1, a 5-fold increase was observed during the first 48 h, but gene expression gradually decreased after 72, 96 and 120 h. Isotype 2 was only expressed during the first 24h, followed by a 130-fold decrease at (time points) 72, 96 and 120 h. The in ovo larval developmental test, in which we exposed initially unembryonated eggs to increased concentrations of TBZ, did affect isotype 1 gene expression but not isotype 2. This assumes that each isotype has specific functions in different life stages. This is in agreement with the 'multi-tubulin' hypothesis, which states that different tubulin isotypes are required for specialised microtubule functions. Isotype 1 is the most likely drug target for BZs, as isotype 2 was only expressed at very low levels later in development. Increasing concentrations of TBZ altered β-tubulin isotype 1 gene expression after exposure of the eggs for five days, but this was not seen for isotype 2.
Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
Publication Date: 2016-02-12 PubMed ID: 26880419DOI: 10.1016/j.molbiopara.2016.02.004Google Scholar: Lookup
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- Journal Article
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Summary
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The research paper investigates the differing expression of two isotypes of the β-tubulin gene in the horse parasite, Parascaris spp, during various stages of development and under exposure to the antiparasitic drug, thiabendazole. The results suggest that each isotype performs specific functions at different life stages and that isotype 1 is more likely to be the target of this class of drugs.
Study’s Context
- The study is formulated in the context of increasing resistance of the horse parasite Parascaris spp to a class of drugs called macrocyclic lactones.
- Maintaining the efficacy of anti-parasitic drugs is important for animal health. Thiabendazole, a benzimidazole class drug, still shows effectiveness against the parasite.
- In response to reports of reducing efficacy of benzimidazoles, the study aimed to investigate aspects of the parasite’s biology related to its interaction with the drug.
Methodology
- The researchers examined the expression of two β-tubulin isotypes, proteins involved in the action mechanism of benzimidazoles, during the development of the parasite.
- Seven time points during embryogenesis and in adult worms were chosen for the investigation.
- An in ovo larval development test using different concentrations of thiabendazole was performed. This experiment aimed to study potential changes in β-tubulin gene expression in response to the drug exposure.
Findings
- In all stages of development, a strong pattern of differential expression between isotype 1 and 2 was found. Isotype 1 was expressed across all stages with varying degrees, while isotype 2 was mainly observed during the early phase of embryogenesis.
- The in ovo larval developmental test under different concentrations of thiabendazole showed impact on isotype 1 gene expression but not on isotype 2, indicating that isotype 1 might be the primary drug target for benzimidazoles.
- The distinct expression patterns of the two β-tubulin isotypes suggest they may have specific roles in different stages of the parasite’s life. This aligns with the ‘multi-tubulin’ hypothesis which theorizes that different tubulin isotypes are necessary for specialized microtubule functions.
Conclusions
- The research reveals that β-tubulin isotype 1 is likely the main target of benzimidazoles in controlling Parascaris spp. This discovery can influence the development of more targeted and effective anti-parasitic drugs in the future.
- The strong pattern of differential expression between isotype 1 and 2 strongly supports the ‘multi-tubulin’ hypothesis.
- The lack of response of isotype 2 to thiabendazole exposure suggests that it may not be a significant factor in drug resistance, unlike isotype 1.
Cite This Article
APA
Tydén E, Skarin M, Andersson-Franko M, Sjöblom M, Höglund J.
(2016).
Differential expression of β-tubulin isotypes in different life stages of Parascaris spp after exposure to thiabendazole.
Mol Biochem Parasitol, 205(1-2), 22-28.
https://doi.org/10.1016/j.molbiopara.2016.02.004 Publication
Researcher Affiliations
- Department of Biomedical Sciences and Veterinary Public Health, Division of Parasitology, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden. Electronic address: Eva.tyden@slu.se.
- Department of Biomedical Sciences and Veterinary Public Health, Division of Parasitology, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden.
- Department of Economics, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden.
- Department of Biomedical Sciences and Veterinary Public Health, Division of Parasitology, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden.
- Department of Biomedical Sciences and Veterinary Public Health, Division of Parasitology, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden.
MeSH Terms
- Animals
- Anthelmintics / pharmacology
- Ascaridida Infections / drug therapy
- Ascaridida Infections / parasitology
- Ascaridoidea / classification
- Ascaridoidea / drug effects
- Ascaridoidea / genetics
- Ascaridoidea / growth & development
- Dose-Response Relationship, Drug
- Drug Resistance
- Gene Expression Regulation, Developmental
- Helminth Proteins / genetics
- Helminth Proteins / metabolism
- Horse Diseases / drug therapy
- Horse Diseases / parasitology
- Horses
- Larva / drug effects
- Larva / genetics
- Protein Isoforms
- Thiabendazole / pharmacology
- Tubulin / genetics
- Tubulin / metabolism
Citations
This article has been cited 5 times.- Cain JL, Nielsen MK. The equine ascarids: resuscitating historic model organisms for modern purposes.. Parasitol Res 2022 Oct;121(10):2775-2791.
- Jones BP, van Vliet AHM, LaCourse EJ, Betson M. Identification of key interactions of benzimidazole resistance-associated amino acid mutations in Ascaris β-tubulins by molecular docking simulations.. Sci Rep 2022 Aug 12;12(1):13725.
- Martin F, Dube F, Karlsson Lindsjö O, Eydal M, Höglund J, Bergström TF, Tydén E. Transcriptional responses in Parascaris univalens after in vitro exposure to ivermectin, pyrantel citrate and thiabendazole.. Parasit Vectors 2020 Jul 9;13(1):342.
- Palma A, Matamoros G, Escobar D, Sánchez AL, Fontecha G. Absence of mutations associated with resistance to benzimidazole in the beta-tubulin gene of Ascaris suum.. Rev Soc Bras Med Trop 2020;53:e20190155.
- Krücken J, Fraundorfer K, Mugisha JC, Ramünke S, Sifft KC, Geus D, Habarugira F, Ndoli J, Sendegeya A, Mukampunga C, Bayingana C, Aebischer T, Demeler J, Gahutu JB, Mockenhaupt FP, von Samson-Himmelstjerna G. Reduced efficacy of albendazole against Ascaris lumbricoides in Rwandan schoolchildren.. Int J Parasitol Drugs Drug Resist 2017 Dec;7(3):262-271.
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