Pharyngeal Pumping and Tissue-Specific Transgenic P-Glycoprotein Expression Influence Macrocyclic Lactone Susceptibility in Caenorhabditis elegans
| Autor: | Gerhard, Alexander P., Krücken, Jürgen, Neveu, Cedric, Charvet, Claude L., Harmache, Abdallah, Von Samson-Himmelstjerna, Georg |
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| Přispěvatelé: | Freie Universität Berlin, Infectiologie et Santé Publique (UMR ISP), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Deutsche Forschungsgemeinschaft (grant number 111144555), Deutsche Forschungsgemeinschaft (grant number 251133687/GRK 2046), Karl-Enigk Foundation (grant number S0229/10019/19), Deutscher Akademischer Austausch Dienst (DAAD) (Project ID 5739054), Procope 2018–2019 Hubert Curien Partnerships program (project number 40582SM), 2017–18 Burroughs Wellcome Fund Collaborative Research Travel Award, Guest Fellowship awarded by Le Studium Institute for Advanced Studies, Orléans, France, Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Macrocyclic lactones
600 Technik Medizin angewandte Wissenschaften::630 Landwirtschaft::630 Landwirtschaft und verwandte Bereiche [SDV]Life Sciences [q-bio] lcsh:R lcsh:Medicine lcsh:RS1-441 P-glycoprotein 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit::616 Krankheiten Caenorhabditis elegans Article lcsh:Pharmacy and materia medica Drug resistance parasitic diseases Parasitology [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie Therapeutik Nematode |
| Zdroj: | Pharmaceuticals Pharmaceuticals, MDPI, 2021, 14 (2), pp.1-17. ⟨10.3390/ph14020153⟩ Pharmaceuticals, Vol 14, Iss 153, p 153 (2021) Volume 14 Issue 2 |
| ISSN: | 1424-8247 |
| DOI: | 10.3390/ph14020153⟩ |
| Popis: | Macrocyclic lactones (MLs) are widely used drugs to treat and prevent parasitic nematode infections. In many nematode species including a major pathogen of foals, Parascaris univalens, resistance against MLs is widespread, but the underlying resistance mechanisms and ML penetration routes into nematodes remain unknown. Here, we examined how the P-glycoprotein efflux pumps, candidate genes for ML resistance, can modulate drug susceptibility and investigated the role of active drug ingestion for ML susceptibility in the model nematode Caenorhabditis elegans. Wildtype or transgenic worms, modified to overexpress P. univalens PGP-9 (Pun-PGP-9) at the intestine or epidermis, were incubated with ivermectin or moxidectin in the presence (bacteria or serotonin) or absence (no specific stimulus) of pharyngeal pumping (PP). Active drug ingestion by PP was identified as an important factor for ivermectin susceptibility, while moxidectin susceptibility was only moderately affected. Intestinal Pun-PGP-9 expression elicited a protective effect against ivermectin and moxidectin only in the presence of PP stimulation. Conversely, epidermal Pun-PGP-9 expression protected against moxidectin regardless of PP and against ivermectin only in the absence of active drug ingestion. Our results demonstrate the role of active drug ingestion by nematodes for susceptibility and provide functional evidence for the contribution of P-glycoproteins to ML resistance in a tissue-specific manner. |
| Databáze: | OpenAIRE |
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