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Home / Equine Research Bank / PLoS One / Genetic variants and increased expression of Parascaris equo...
PloS one2013; 8(4); e61635; doi: 10.1371/journal.pone.0061635

Genetic variants and increased expression of Parascaris equorum P-glycoprotein-11 in populations with decreased ivermectin susceptibility.

Abstract: Macrocyclic lactones (MLs) represent the major drug class for control of parasitic infections in humans and animals. However, recently reports of treatment failures became more frequent. In addition to human and ruminant parasitic nematodes this also is the case for the horse-nematode Parascaris equorum. Nevertheless, to date the molecular basis of ML resistance is still not understood. Unspecific resistance mechanisms involving transporters such as P-glycoproteins (Pgps) are expected to contribute to ML resistance in nematodes. Here, complete sequences of two P. equorum Pgps were cloned and identified as orthologs of Caenorhabditis elegans Ppg-11 and an unnamed Caenorhabditis briggsae Pgp designated as Pgp-16 using phylogenetic analysis. Quantitative real-time PCR was used to compare expression between tissues. Significantly higher PeqPgp-11 expression was found in the gut for both genders, whereas for PeqPgp-16 the body wall was identified as predominant expression site. Furthermore, Pgps were analyzed regarding their participation in resistance development. Using SeqDoC analyses, Pgp-sequences of P. equorum populations with different ML susceptibility were compared. This approach revealed three single nucleotide polymorphisms (SNPs) causing missense mutations in the PeqPgp-11 sequence which correlated with decreased ML susceptibility. However, no resistance associated differences in mRNA expression levels were detected between embryonated eggs of these populations. In contrast, comparison of two pre-adult groups with different ivermectin (IVM) susceptibility revealed the presence of the three SNPs and in addition statistically significant PeqPgp-11 overexpression in the group of worms with reduced susceptibility. These results indicate that Pgp-11 might be involved in IVM resistance in P. equorum as it shows increased expression in an IVM exposed life-cycle stage of an IVM resistant population as well as occurrence of putatively resistance associated SNPs in populations with reduced IVM susceptibility. These SNPs are promising diagnostic candidates for detection of ML resistance with potential also for other parasitic nematode species.
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Publication Date: 2013-04-24 PubMed ID: 23637871PubMed Central: PMC3634834DOI: 10.1371/journal.pone.0061635Google Scholar: Lookup
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  • Journal Article
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  • Non-U.S. Gov't

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.

This study explores the potential role of certain genetic variants of the Parascaris equorum P-glycoprotein-11 in decreasing the effectiveness of a widely used anti-parasitic drug, Ivermectin. Collecting sequences of P-glycoproteins from various sources of infection and analyzing their association with drug resistance, the research identified three specific genetic mutations that appear to contribute to decreased susceptibility to the drug.

Background and Purpose of the Study

  • The study is focused on Macrocyclic lactones (MLs), a major class of drugs used for treating parasitic infections in humans and animals. Overall effectiveness of these drugs is reportedly decreasing.
  • The researchers take a close look at Parascaris equorum, a parasitic nematode specific to horses, which seems to have developed resistance to these drugs.
  • The main aim of the study is to understand the molecular reasons behind this resistance. The researchers hypothesize that the P-glycoproteins (Pgps) present in these parasites somehow contribute to the development of drug resistance.

Methodology

  • The research team clones the complete sequences of two P. equorum P-glycoproteins (PeqPgp-11 and PeqPgp-16), which they identify through phylogenetic analysis.
  • Using real-time PCR, they compare the expression of these sequences in various tissues of the parasite. They discover a higher expression of PeqPgp-11 in the gut and a higher expression of PeqPgp-16 in the body wall.
  • SeqDoC analyses are used to compare Pgp-sequences in populations with varying susceptibility to MLs.

Key Findings

  • Three specific single nucleotide polymorphisms (SNPs), or genetic mutations, in the PeqPgp-11 sequence were found to correlate with reduced susceptibility to MLs.
  • The researchers discovered no significant change in mRNA expression levels between different populations.
  • However, in pre-adult groups with different ivermectin (IVM) susceptibility, the research detected the presence of these three SNPs and also found increased expression of PeqPgp-11 in populations with reduced susceptibility.

Conclusions

  • The study concludes that these three SNPs and overexpression of PeqPgp-11 in the P. equorum nematode might be contributing to its resistance to the IVM drug.
  • The SNPs found in this study are likely to serve as critical diagnostic markers for detecting drug resistance and may also apply to other species of parasitic nematodes.

Cite This Article

APA
Janssen IJ, Krücken J, Demeler J, Basiaga M, Kornaś S, von Samson-Himmelstjerna G. (2013). Genetic variants and increased expression of Parascaris equorum P-glycoprotein-11 in populations with decreased ivermectin susceptibility. PLoS One, 8(4), e61635. https://doi.org/10.1371/journal.pone.0061635

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 8
Issue: 4
Pages: e61635

Researcher Affiliations

Janssen, I Jana I
  • Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Germany.
Krücken, Jürgen
    Demeler, Janina
      Basiaga, Marta
        Kornaś, Sławomir
          von Samson-Himmelstjerna, Georg

            MeSH Terms

            • ATP Binding Cassette Transporter, Subfamily B / genetics
            • Alleles
            • Animals
            • Antinematodal Agents / pharmacology
            • Ascaridoidea / classification
            • Ascaridoidea / drug effects
            • Ascaridoidea / genetics
            • Drug Resistance / genetics
            • Female
            • Gene Expression
            • Gene Expression Regulation / drug effects
            • Gene Frequency
            • Genetic Variation
            • Horses / parasitology
            • Ivermectin / pharmacology
            • Male
            • Organ Specificity / genetics
            • Phylogeny
            • Polymorphism, Single Nucleotide
            • RNA, Messenger / genetics

            Conflict of Interest Statement

            Competing Interests: The authors have declared that no competing interests exist.

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