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

J. Janssen , J. Krücken , J. Demeler , Marta Basiaga , Sławomir Kornaś , G. von Samson Himmelstjerna

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.
Author J. Janssen
J. Janssen,,
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, J. Krücken
J. Krücken,,
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, J. Demeler
J. Demeler,,
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, Marta Basiaga (DoAS / DoZaE)
Marta Basiaga,,
- Department of Zoology and Ecology
, Sławomir Kornaś (DoAS / DoZaE)
Sławomir Kornaś,,
- Department of Zoology and Ecology
, G. von Samson Himmelstjerna
G. von Samson Himmelstjerna,,
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Journal seriesPlos One, ISSN 1932-6203, (A 35 pkt)
Issue year2013
Vol8
No4
Pages1-10
Publication size in sheets0.5
DOIDOI:10.1371/journal.pone.0061635
URL http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061635
Internal identifierWHiBZ/2013/11
Languageen angielski
LicenseJournal (articles only); author's original; Uznanie Autorstwa (CC-BY); after publication
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Genetic Variants and Increased Expression of Parascaris equorum P-glycoprotein-11 in Populations with Decreased Ivermectin Susceptibility of 17-04-2019
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Score (nominal)40
ScoreMinisterial score = 40.0, 26-07-2017, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 26-07-2017, ArticleFromJournal
Citation count*14 (2016-01-21)
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