Repeated Ivermectin Treatment Induces Ivermectin Resistance in Strongyloides ratti by Upregulating the Expression of ATP-Binding Cassette Transporter Genes

Ivermectin (IVM) is a widely used anthelmintic. However, with widespread use comes the risk of the emergence of IVM resistance, particularly in strongyloidiasis. Adenosine triphosphate (ATP)-binding cassette (ABC) transporter genes play an important role in the IVM-resistance mechanism. Here, we aim...

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Bibliographic Details
Published in:The American journal of tropical medicine and hygiene 2021-10, Vol.105 (4), p.1117-1123
Main Authors: Sengthong, Chatchawan, Yingklang, Manachai, Intuyod, Kitti, Haonon, Ornuma, Pinlaor, Porntip, Jantawong, Chanakan, Hongsrichan, Nuttanan, Laha, Thewarach, Anutrakulchai, Sirirat, Cha'on, Ubon, Sithithaworn, Paiboon, Pinlaor, Somchai
Format: Article
Language:English
Subjects:
Animals
Antiparasitic Agents - administration & dosage
Antiparasitic Agents - pharmacology
ATP-Binding Cassette Transporters - genetics
ATP-Binding Cassette Transporters - metabolism
Drug Administration Schedule
Drug dosages
Drug Resistance
Gene Expression Regulation - drug effects
Ivermectin - administration & dosage
Ivermectin - pharmacology
Male
Rats
Strongyloides ratti - drug effects
Up-Regulation
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Summary:Ivermectin (IVM) is a widely used anthelmintic. However, with widespread use comes the risk of the emergence of IVM resistance, particularly in strongyloidiasis. Adenosine triphosphate (ATP)-binding cassette (ABC) transporter genes play an important role in the IVM-resistance mechanism. Here, we aimed to establish an animal experimental model of IVM resistance by frequent treatment of Strongyloides ratti with subtherapeutic doses of IVM, resistance being evaluated by the expression levels of ABC transporter genes. Rats infected with S. ratti were placed in experimental groups as follows: 1) untreated control (control); 2) treated with the mutagen ethyl methanesulfonate (EMS); 3) injected with 100 µg/kg body weight of IVM (IVM); 4) treated with a combination of EMS and IVM (IVM+EMS). Parasites were evaluated after four generations. Extent of IVM resistance was assessed using IVM sensitivity, larval development, and expression of ABC genes. By the F4 generation, S. ratti in the IVM group exhibited significantly higher levels of IVM resistance than did other groups according to in vitro drug-sensitivity tests and inhibition of larval development (IC50 = 36.60 ng/mL; 95% CI: 31.6, 42.01). Expression levels of ABC isoform genes (ABCA, ABCF, and ABCG) were statistically significantly higher in the IVM-resistant line compared with the susceptible line. In conclusion, IVM subtherapeutic doses induced IVM resistance in S. ratti by the F4 generation with corresponding upregulation of some ABC isoform genes. The study provides a model for inducing and assessing drug resistance in Strongyloides.
ISSN:0002-9637
1476-1645
DOI:10.4269/ajtmh.21-0377