Publikationsdatenbank

The role of nematode P-glycoproteins in the mechanism of macrocyclic lactone resistance (2021)

Art

Hochschulschrift

Autor

Gerhard, Alexander Paul (WE 13)

Quelle

Berlin, 2021 — VI, 185 Seiten

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/31742

Kontakt

Institut für Parasitologie und Tropenveterinärmedizin

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 62310
parasitologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Control of veterinary and human parasitic nematodes relies heavily on chemotherapy with anthelmintics but drug resistance is a growing problem. Against the widely used macrocyclic lactones (MLs), drug resistance has emerged in several nematode species and this is a particular challenge in parasites of ruminants and horses. For instance, ML resistance is globally widespread in an important pathogen of foals, Parascaris univalens. In order to find a sustainable solution for this problematic trend, a good knowledge of the underlying resistance mechanisms is considered imperative but the mechanisms of ML resistance are mostly unknown. Among other mechanisms, ATP-binding-cassette (ABC)-transporters and particularly members of the ABCB subfamily, the P-glycoproteins (Pgps), have been proposed as contributors to ML resistance in several nematode species but their functional role remains to be elucidated. In this PhD project, the complete Pgp repertoire in the horse roundworm P. univalens was characterized by transcriptome-guided RT-PCR and Sanger sequencing identifying a total of ten Pgps. Using a diverse set of transcriptome resources, the tissue expression patterns of Pgps were characterized in P. univalens and in Caenorhabditis elegans showing strong intestinal and moderate epidermal expression. No inducibility of individual P. univalens Pgp expression was found by examining a novel transcriptome generated from adult P. univalens incubated with ivermectin or a control. To investigate the function of nematode Pgps and their substrate range, heterologous expression of P. univalens Pgps in different model organisms was employed. In a yeast model the interaction with different anthelmintics was characterized. In C. elegans the uptake routes and barriers into the worm were characterized by selectively inducing drug ingestion. At the intestinal and epidermal barrier, transgenic Pgp expression reduced susceptibility to ivermectin and moxidectin. In conclusion, this work demonstrates that Pgps are likely to be contributors to ML resistance and indicates that their protective effect results from enhancing barrier function. In order to reverse Pgp-mediated resistance, preliminary analyses to identify inhibitors specific to nematode Pgps were performed and first results instigate a more detailed characterization.