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Parasites & vectors2022; 15(1); 158; doi: 10.1186/s13071-022-05260-4

Ivermectin-induced gene expression changes in adult Parascaris univalens and Caenorhabditis elegans: a comparative approach to study anthelminthic metabolism and resistance in vitro.

Abstract: The nematode Parascaris univalens is one of the most prevalent parasitic pathogens infecting horses but anthelmintic resistance undermines treatment approaches. The molecular mechanisms underlying drug activity and resistance remain poorly understood in this parasite since experimental in vitro models are lacking. The aim of this study was to evaluate the use of Caenorhabditis elegans as a model for P. univalens drug metabolism/resistance studies by a comparative gene expression approach after in vitro exposure to the anthelmintic drug ivermectin (IVM). Methods: Twelve adult P. univalens worms in groups of three were exposed to ivermectin (IVM, 10 M, 10 M, 10 M) or left unexposed for 24 h at 37 °C, and total RNA, extracted from the anterior end of the worms, was sequenced using Illumina NovaSeq. Differentially expressed genes (DEGs) involved in metabolism, transportation, or gene expression with annotated Caernorhabditis elegans orthologues were identified as candidate genes to be involved in IVM metabolism/resistance. Similarly, groups of 300 adult C. elegans worms were exposed to IVM (10 M, 10 M and 10 M) or left unexposed for 4 h at 20 °C. Quantitative RT-PCR of RNA extracted from the C. elegans worm pools was used to compare against the expression of selected P. univalens candidate genes after drug treatment. Results: After IVM exposure, 1085 DEGs were found in adult P. univalens worms but the relative gene expression changes were small and large variabilities were found between different worms. Fifteen of the DEGs were chosen for further characterization in C. elegans after comparative bioinformatics analyses. Candidate genes, including the putative drug target lgc-37, responded to IVM in P. univalens, but marginal to no responses were observed in C. elegans despite dose-dependent behavioral effects observed in C. elegans after IVM exposure. Thus, the overlap in IVM-induced gene expression in this small set of genes was minor in adult worms of the two nematode species. Conclusions: This is the first time to our knowledge that a comparative gene expression approach has evaluated C. elegans as a model to understand IVM metabolism/resistance in P. univalens. Genes in P. univalens adults that responded to IVM treatment were identified. However, identifying conserved genes in P. univalens and C. elegans involved in IVM metabolism/resistance by comparing gene expression of candidate genes proved challenging. The approach appears promising but was limited by the number of genes studied (n = 15). Future studies comparing a larger number of genes between the two species may result in identification of additional candidate genes involved in drug metabolism and/or resistance.
© 2022. The Author(s).
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Publication Date: 2022-05-05 PubMed ID: 35513885PubMed Central: PMC9074254DOI: 10.1186/s13071-022-05260-4Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research study explores the molecular mechanisms of ivermectin (an anti-parasitic drug) metabolism and resistance in Parascaris univalens, a common parasitic worm infecting horses. The study compares gene expression changes induced by ivermectin in P. univalens and Caenorhabditis elegans, a model organism often used in biological research.

Research Objectives and Methodology

The researchers aimed to understand how ivermectin affects P. univalens and whether C. elegans can serve as an appropriate model for studying ivermectin treatment in P. univalens. They used comparative gene expression techniques post-exposure to ivermectin in both worms.

  • P. univalens and C. elegans worms underwent exposure to different ivermectin concentrations for 24 hours and 4 hours at respective temperatures of 37°C and 20°C.
  • Total RNA was then extracted and sequenced to identify differentially expressed genes (DEGs).
  • Particular attention was given to DEGs involved in metabolism, transport, or gene expression which had annotated C. elegans orthologues (equivalent genes).
  • Quantitative reverse transcriptase–polymerase chain reaction (RT-qPCR) was performed on RNA from C. elegans to compare the expression of selected genes to their counterparts in P. univalens after ivermectin exposure.

Results

Following ivermectin treatment, the researchers identified 1085 DEGs in P. univalens. However, the gene expression changes were minor, and considerable variability was observed between different worm samples. After some comparative bioinformatics analysis, 15 of these DEGs were selected for further characterization in C. elegans.

  • These candidate genes, including the putative drug target lgc-37, demonstrated response to ivermectin in P. univalens, but little to no response in C. elegans, despite the drug causing dose-dependent behavioral effects in the latter.
  • The researchers hence concluded that the overlap in ivermectin-induced gene expression changes between P. univalens and C. elegans was minor.

Conclusions and Future Directions

This study was the first to use a comparative gene expression approach to assess if C. elegans can serve as a model for understanding ivermectin metabolism/resistance in P. univalens. While the scientists identified P. univalens genes that responded to ivermectin treatment, finding conserved genes in both P. univalens and C. elegans proved challenging.

  • The research showed potential but was limited by the number of genes studied.
  • The authors suggested that future investigations comparing more genes between the two worm species may result in the identification of more candidate genes involved in drug metabolism and resistance.

Cite This Article

APA
Dube F, Hinas A, Roy S, Martin F, Åbrink M, Svärd S, Tydén E. (2022). Ivermectin-induced gene expression changes in adult Parascaris univalens and Caenorhabditis elegans: a comparative approach to study anthelminthic metabolism and resistance in vitro. Parasit Vectors, 15(1), 158. https://doi.org/10.1186/s13071-022-05260-4

Publication

Parasites & vectors
ISSN: 1756-3305
NlmUniqueID: 101462774
Country: England
Language: English
Volume: 15
Issue: 1
Pages: 158
PII: 158

Researcher Affiliations

Dube, Faruk
  • Division of Parasitology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7036, 750 07, Uppsala, Sweden. faruk.dube@slu.se.
Hinas, Andrea
  • Department of Cell and Molecular Biology, Uppsala University, 751 24, Uppsala, Sweden.
Roy, Shweta
  • Department of Cell and Molecular Biology, Uppsala University, 751 24, Uppsala, Sweden.
Martin, Frida
  • Division of Parasitology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7036, 750 07, Uppsala, Sweden.
Åbrink, Magnus
  • Section of Immunology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7036, 750 07, Uppsala, Sweden.
Svärd, Staffan
  • Department of Cell and Molecular Biology, Uppsala University, 751 24, Uppsala, Sweden.
Tydén, Eva
  • Division of Parasitology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7036, 750 07, Uppsala, Sweden.

MeSH Terms

  • Animals
  • Anthelmintics / therapeutic use
  • Ascaridoidea
  • Caenorhabditis elegans
  • Drug Resistance / genetics
  • Gene Expression
  • Horses
  • Ivermectin / therapeutic use
  • RNA / metabolism

Grant Funding

  • 2018-01049 / Svenska Forskningsru00e5det Formas

Conflict of Interest Statement

The authors declare that they have no competing interests.

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Citations

This article has been cited 6 times.
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