Evidence of p-glycoprotein sequence diversity in cyathostomins.
Abstract: P-glycoproteins (Pgps) are adenosine triphosphate-binding transporter proteins thought to be associated with multi-drug resistance in mammals and protozoans and have been suggested to be involved in the mechanism of ivermectin (IVM) resistance in Haemonchus contortus. Until now, resistance to IVM has not been reported in cyathostomins in horses in spite of its widespread and frequent use. Reasons for this might be differences in the molecular mechanism of the development of resistance. Based on this hypothesis, the present study was carried out to find homologues of Pgp in cyathostomins. A 416-bp polymerase chain reaction (PCR) product was generated using complementary DNA (cDNA) of Cylicocyclus elongatus and Cylicocyclus insigne and degenerate primers, located in the conserved Pgp nucleotide-binding domains. Resulting PCR products showed interspecific nucleotide and amino acid sequence identities of 73.3 and 76.8%, respectively. Specific primers were designed based on the Cc. elongatus sequence, and a PCR product of 268-bp was amplified from cDNA of single adults of Cylicocyclus radiatus, Cc. insigne, Cylicocyclus nassatus, Cc. elongatus, Cylicostephanus hybridus (2 individuals), Cylicostephanus goldi, Cyathostomum pateratum, Cyathostomum coronatum, and Cyathostomum catinatum. Two clusters of sequences were found representing 2 different internucleotide-binding domains (IBDs). A further distinct IBD is represented by the 416-bp PCR product of Cc. insigne. Therefore, a total of 3 clearly different sequences of the IBD were cloned and sequenced, suggesting that at least 2 Pgp genes exist in cyathostomins.
Publication Date: 2004-11-26 PubMed ID: 15562598DOI: 10.1645/GE-3312Google Scholar: Lookup
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- Journal Article
Summary
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This research is focused on exploring the diversity of a specific protein known as P-glycoproteins (Pgps) in cyathostomins, a type of parasitic worm in horses, and its role in being resistant to a common medication used in its treatment, ivermectin (IVM).
Background and Purpose
- P-glycoproteins are known to be associated with multi-drug resistance in mammals and protozoans and have suggested involvement in resistance to IVM in Haemonchus contortus, another parasitic worm.
- Resistance to IVM in cyathostomins has not been reported previously, despite frequent usage of this medication.
- The study hypothesized the resistance might be due to differences at a molecular level. Consequently, this research was initiated to find Pgp equivalents in cyathostomins.
Methodology
- Complementary DNA (cDNA) of two particular types of cyathostomins, Cylicocyclus elongatus and Cylicocyclus insigne, were isolated and employed with degenerate primers to generate a 416-base pair (bp) polymerase chain reaction (PCR) product. These primers target the conserved nucleotide-binding domains of Pgp.
- Following the generation of PCR products, interspecific nucleotide and amino acid sequence identities were analyzed. This resulted in identities of 73.3% and 76.8%, respectively.
Results
- After obtaining the sequence from Cc. elongatus, specific primers were formulated and used to amplify a 268-bp PCR product from the cDNA of single adults of various types of cyathostomins, including Cylicocyclus radiatus and Cylicostephanus hybridus, among others.
- The analysis led to the discovery of two clusters of sequences, symbolizing two distinct internucleotide-binding domains (IBDs). An additional unique IBD was represented by the 416-bp PCR product of Cc. insigne.
Conclusion
- The study findings disclosed three clearly different sequences of IBD. This implies that there exist at least two Pgp genes within the cyathostomins, indicating the presence of a kind of genetic diversity.
- The relationship of these diverse Pgps on the resistance or susceptibility of the cyathostomins to ivermectin will need further investigation.
Cite This Article
APA
Drogemuller M, Schnieder T, von Samson-Himmelstjerna G.
(2004).
Evidence of p-glycoprotein sequence diversity in cyathostomins.
J Parasitol, 90(5), 998-1003.
https://doi.org/10.1645/GE-3312 Publication
Researcher Affiliations
- Institute of Parasitology, Hannover School of Veterinary Medicine, Buenteweg 17, D-30559 Hannover, Germany.
MeSH Terms
- ATP Binding Cassette Transporter, Subfamily B / chemistry
- ATP Binding Cassette Transporter, Subfamily B / genetics
- Amino Acid Sequence
- Animals
- Anthelmintics / pharmacology
- Base Sequence
- Benzimidazoles / pharmacology
- DNA, Complementary / chemistry
- DNA, Helminth / chemistry
- Drug Resistance / genetics
- Genetic Variation
- Horses
- Ivermectin / pharmacology
- Polymerase Chain Reaction / veterinary
- RNA, Helminth / genetics
- RNA, Helminth / isolation & purification
- RNA, Messenger / genetics
- RNA, Messenger / isolation & purification
- Sequence Alignment / veterinary
- Strongyle Infections, Equine / parasitology
- Strongyloidea / chemistry
- Strongyloidea / drug effects
- Strongyloidea / genetics
Citations
This article has been cited 4 times.- Peachey LE, Pinchbeck GL, Matthews JB, Burden FA, Lespine A, von Samson-Himmelstjerna G, Krücken J, Hodgkinson JE. P-glycoproteins play a role in ivermectin resistance in cyathostomins.. Int J Parasitol Drugs Drug Resist 2017 Dec;7(3):388-398.
- Raza A, Kopp SR, Bagnall NH, Jabbar A, Kotze AC. Effects of in vitro exposure to ivermectin and levamisole on the expression patterns of ABC transporters in Haemonchus contortus larvae.. Int J Parasitol Drugs Drug Resist 2016 Aug;6(2):103-15.
- Janssen IJ, Krücken J, Demeler J, Basiaga M, Kornaś S, von Samson-Himmelstjerna G. Genetic variants and increased expression of Parascaris equorum P-glycoprotein-11 in populations with decreased ivermectin susceptibility.. PLoS One 2013;8(4):e61635.
- Cobb R, Boeckh A. Moxidectin: a review of chemistry, pharmacokinetics and use in horses.. Parasit Vectors 2009 Sep 25;2 Suppl 2(Suppl 2):S5.
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