Haemonchus contortus ABC transporters linked to macrocyclic lactone resistance
Bibliographic record
Abstract
Haemonchus contortus is a parasitic nematode distributed all around the world where ruminants graze and decreases animal production. In order to control this veterinary helminth, anthelmintic drugs are still the main strategy in veterinary medicine. One particular anthelmintic class is the macrocyclic lactones (MLs), which has remarkable efficacy against endo and ectoparasites in animal and human health. Unfortunately, due to the continuous use of the MLs against parasitic nematodes, including H. contortus, has led to drug resistance, that limits their use. In H. contortus, one of the resistance mechanisms involved could be the over expression of P-glycoproteins (PGPs) and possibly other nematode transporters, which belong to the ATP-Binding-Cassette (ABC) transporter protein family. The activity of the ABC transporters is the extrusion of many unrelated compounds across the cell membrane. In the host, these plasma membrane proteins are expressed in different organs and tissues influencing the bioavailability and pharmacokinetics of different substrates including the MLs. In H. contortus and other nematodes, some ABC transporters have shown a consistent link with ML resistance. In addition, studies characterizing the interaction between mammalian ABC transporters with ML such as avermectins, have established a strong interaction between these compounds and PGP activity, transporting these drugs and contributing to their elimination. The goal of this project was the characterization of some H. contortus P-glycoproteins (Hco-PGP-2, Hco-PGP-9.1 and Hco-PGP-16) and their interaction with MLs such as avermectins and moxidectin in order to elucidate if these transporters may play a role in ML resistance in this parasite. These Hco-PGPs were expressed in mammalian cells and their functional activity was characterized, and localization inside the worm was determined in some cases. In the host mammalian cells, these nematode transporters were localized in the plasma membrane. After functional studies were carried out, using fluorophore probes to test the activity of these Hco-PGPs. Furthermore, the interaction with the different MLs was studied. There was found a strong interaction of the avermectins (abamectin, ivermectin and ivermectin aglycone) with the three H. contortus PGPs that were characterized, whereas the interaction with moxidectin was markedly different, suggesting a weaker interaction of these nematode transporters with moxidectin. In addition, the expression of two H. contortus PGPs was localized in adult worms. Hco-PGP-2 was expressed in the head region, particularly in the pharynx, nerve chords around the pharynx, in the deirids and in the first portion of the intestine. On the other hand, Hco-PGP-9.1 was localized in the female reproductive system, at the level of the uterus. These results indicate that these H. contortus PGPs may interact with, and possibly efflux, the avermectins such as abamectin and ivermectin but less with moxidectin. The location of these transporters in the adult parasite may suggest a role as efflux pumps for the avermectins in key tissues where the glutamate-gated chloride channels, ML target receptors, are expressed and thus these PGPs may contribute to the elimination of the avermectins in resistant H. contortus parasites. This work provides new information on the interaction and potential involvement of nematode transporters with ML anthelmintics in drug resistance. This knowledge may be useful in planning how to modulate their function in order to improve ML anthelmintic chemotherapy.
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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".