Genetic analysis of a relationship between macrocyclic lactone and benzimidazole anthelmintic selection on Haemonchus contortus
Bibliographic record
Abstract
OBJECTIVES: We have found that in a laboratory strain of the nematode parasite of ruminants, Haemonchus contortus, repeated ivermectin treatment, in vivo in sheep, selected against TTC, coding for Phe, and for TAC, coding for Tyr, at codon 200 in beta-tubulin isotype 1. This 200Tyr single nucleotide polymorphism (SNP) has been associated with benzimidazole anthelmintic resistance. In this study, we investigated the alpha-tubulin and beta-tubulin sequences of 17 different field and laboratory strains/isolates of H. contortus with known treatment history and status for susceptibility or resistance to macrocyclic lactone (ML) or benzimidazole anthelmintics. BASIC METHODS: DNA (genomic or cDNA) from 10 to 32 male parasites was sequenced for alpha-tubulin or beta-tubulin for each strain/isolate and the frequency of coding SNPs was compared between the different strains/isolates with known treatment history and drug resistance status. MAIN RESULTS: We have analyzed alpha-tubulin and beta-tubulin isotypes 1 and 2 genes from the different H. contortus strains/isolates and found that repeated ivermectin or moxidectin (both ML anthelmintics) use changes the frequency of beta-tubulin isotype 1 alleles and selects for the following SNPs: either from TTC (Phe) to TAC (Tyr) at codon 200 or codon 167, or from GCA (Ala) to GAA (Glu) at codon 198. 200Tyr and 167Tyr were associated with GTT (Val) or CTC/CTT (Leu) at codon 368, whereas 200Phe or 167Phe were associated with either ATT (Ile) or GTT (Val) at codon 368 in beta-tubulin isotype 1. The SNPs 200Tyr, 167Tyr in beta-tubulin isotype 1 have been described to confer benzimidazole resistance in nematodes and recently 198Ala has also been associated with benzimidazole resistance. CONCLUSIONS: Although MLs exert their antiparasitic effect through binding to ligand-gated chloride channels, benzimidazoles interact with beta-tubulin. These genetic analyses indicate that there is a correlation between exposure and/or resistance to MLs and an increase in the frequency of the beta-tubulin alleles containing codons, which are determinant for benzimidazole resistance. ML use may predispose parasitic nematodes to benzimidazole resistance. This has major implications for parasite control programs dependent on MLs/benzimidazole rotations and on the use of ML/benzimidazole combination therapy, such as for human lymphatic filariasis and nematode control in ruminant livestock.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".