Effects of in vitro exposure to ivermectin and levamisole on the expression patterns of ABC transporters in Haemonchus contortus larvae
| Autor: | Abdul Jabbar, Ali Raza, Andrew C. Kotze, Steven Kopp, Neil H. Bagnall |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Transcription Genetic 030231 tropical medicine Population Resistance Drug Resistance ATP-binding cassette transporter Drug resistance Pharmacology P-glycoprotein Article Microbiology lcsh:Infectious and parasitic diseases 03 medical and health sciences 0302 clinical medicine Haemonchus contortus Gene expression Animals Pharmacology (medical) lcsh:RC109-216 education Anthelmintics education.field_of_study Ivermectin biology Gene Expression Profiling biology.organism_classification Multiple drug resistance 030104 developmental biology Infectious Diseases Gene Expression Regulation Levamisole ABC transporters Larva biology.protein ATP-Binding Cassette Transporters Haemonchus Parasitology Efflux |
| Zdroj: | International Journal for Parasitology: Drugs and Drug Resistance, Vol 6, Iss 2, Pp 103-115 (2016) International Journal for Parasitology: Drugs and Drug Resistance |
| ISSN: | 2211-3207 |
| Popis: | This study investigated the interaction of ATP binding cassette (ABC) transport proteins with ivermectin (IVM) and levamisole (LEV) in larvae of susceptible and resistant isolates of Haemonchus contortus in vitro by measuring transcription patterns following exposure to these anthelmintics. Furthermore, we studied the consequences of drug exposure by measuring the sensitivity of L3 to subsequent exposure to higher drug concentrations using larval migration assays. The most highly transcribed transporter genes in both susceptible and resistant L3 were pgp-9.3, abcf-1, mrp-5, abcf-2, pgp-3, and pgp-10. The resistant isolate showed significantly higher transcription of pgp-1, pgp-9.1 and pgp-9.2 compared to the susceptible isolate. Five P-gp genes and the haf-6 gene showed significantly higher transcription (up to 12.6-fold) after 3 h exposure to IVM in the resistant isolate. Similarly, five P-gp genes, haf-6 and abcf-1 were transcribed at significantly higher levels (up to 10.3-fold) following 3 h exposure to LEV in this isolate. On the other hand, there were no significant changes in transcriptional patterns of all transporter genes in the susceptible isolate following 3 and 6 h exposure to IVM or LEV. In contrast to these isolate-specific transcription changes, both isolates showed an increase in R-123 efflux following exposure to the drugs, suggesting that the drugs stimulated activity of existing transporter proteins in both isolates. Exposure of resistant larvae to IVM or LEV resulted, in some instances, in an increase in the proportion of the population able to migrate at the highest IVM concentrations in subsequent migration assays. The significant increase in transcription of some ABC transporter genes following 3 h exposure to both IVM and LEV in the resistant isolate only, suggests that an ability to rapidly upregulate protective pathways in response to drugs may be a component of the resistance displayed by this isolate. Graphical abstract Highlights • We studied interaction of anthelmintics with ABC transporters in Haemonchus contortus. • pgp-1, 2, -9.1, -10, and -11 and haf-6 up-regulated after 3 h exposure to ivermectin. • Up-regulation occurred in a drug-resistant isolate but not in a -susceptible isolate. • A proportion of the drug exposed larvae showed tolerance to subsequent drug treatment. • Rapid up-regulation of transporters may be component of resistance in parasitic nematodes. |
| Databáze: | OpenAIRE |
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