Haemonchus contortus ABC transporters linked to macrocyclic lactone resistance
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».