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Published on: July 1, 2018
Pharyngeal Pumping and Tissue-Specific Transgenic P-Glycoprotein Expression Influence Macrocyclic Lactone
Alexander P Gerhard1, Jürgen Krücken1, Cedric Neveu2
1Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, 14163 Berlin, Germany.
Abstract:
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.
Insights
Nematode resistance to macrocyclic lactones (MLs) is a growing problem. This study reveals that active drug ingestion and P-glycoprotein efflux pumps influence ML drug susceptibility in nematodes.
Area of Science:
- Veterinary Parasitology
- Molecular Biology
- Drug Resistance Mechanisms
Background:
- Macrocyclic lactones (MLs) are crucial for treating nematode infections, but widespread resistance is a significant challenge.
- Mechanisms of ML resistance and drug entry routes into nematodes are not fully understood.
- P-glycoprotein (PGP) efflux pumps are implicated in ML resistance.
Purpose of the Study:
- To investigate how P-glycoprotein efflux pumps modulate drug susceptibility in nematodes.
- To determine the role of active drug ingestion in ML susceptibility.
- To explore tissue-specific functions of PGP in ML resistance.
Main Methods:
- Utilized the model nematode *Caenorhabditis elegans*, including wildtype and transgenic strains overexpressing *Parascaris univalens* PGP-9 (Pun-PGP-9) in the intestine or epidermis.
- Incubated worms with ivermectin or moxidectin under conditions with (bacteria or serotonin) or without pharyngeal pumping (PP)-mediated active drug ingestion.
- Assessed drug susceptibility based on worm survival and response.
Main Results:
- Active drug ingestion via pharyngeal pumping significantly impacts ivermectin susceptibility, with a moderate effect on moxidectin.
- Intestinal Pun-PGP-9 conferred protection against both ivermectin and moxidectin, but only when active ingestion was stimulated.
- Epidermal Pun-PGP-9 provided moxidectin protection irrespective of pharyngeal pumping and ivermectin protection in the absence of active ingestion.
Conclusions:
- Active drug ingestion is a critical factor influencing nematode susceptibility to MLs.
- P-glycoprotein efflux pumps contribute to ML resistance in a tissue-specific manner, highlighting complex interactions with drug uptake pathways.
- Findings provide functional evidence for PGP's role in ML resistance and inform strategies to combat parasitic nematode infections.
