Prof. Dr. Georg von Samson-Himmelstjerna, Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin

Parasitic nematodes represent the most often occurring helminth infections both in humans as well as in animals. While human infections mainly occur in LMIC animal infections also ubiquitously affect animals in all countries. Intestinal roundworms (ascarids) are both, highly prevalent and pathogenic particularly in juvenile hosts. While neither for humans nor for animals any vaccines are available, treatment and control heavily depend on the use of anthelmintics. This has led to the evolution of anthelmintic resistance in many parasitic nematode species including ascarids. Benzimidazoles (BZ) are the by far most frequently used anthelmintics to treat humans against ascarid infections and they also are often used in animals, particularly since macrocyclic lactones as another major drug class are long facing widespread resistance for example in equine ascarids (1,2). In contrast to other parasitic nematodes such as trichostrongylids, in ascarids drug target associated changes (i.e., beta-tubulin sequence polymorphisms) do not appear to be associated with BZ resistance (3,4). Drug efflux or metabolizing pathways (DEMP) based on e.g., cytochrome P450 (CYP) enzymes, UDPglucuronosyl/ glucosyl transferase (UGT) enzymes or P-glycoprotein (Pgp) transmembrane pumps, respectively, represent potential alternative resistance mechanisms for BZ resistance particularly in ascarids. We have previously employed qRT-PCR and transcriptomic analyses in parasitic nematodes to investigate the role of CYPs for anthelmintic susceptibility (5,6) and the heterologous expression of ascarid Pgps in the model nematode Caenorhabditis elegans to functionally investigate anthelmintic efflux effects (7).

Following these approaches the present DR projects will for the first time allow us to molecularly and functionally examine selected anthelmintic metabolizing and drug transporter genes from Ascaris spp. concerning their influence on BZ susceptibility. Furthermore, by employing recently obtained innovative as well as established compounds we will strive to identify putative nematode-specific DEMP inhibitors aiming at the reversal of BZ resistance. In parallel, we will obtain Ascaris and A. galli field samples, which will be studied during the second phase of this RTG to assess their BZ-susceptibility phenotype using established in vitro assays. This material will then be the basis for investigations on the occurrence and relevance of the previously identified BZ-susceptibility associated genes in the field.

References:
1) von Samson-Himmelstjerna et al. 2007, doi: 10.1016/j.vetpar.2006.09.036; 2) Wolstenholme et al. 2024, doi: 10.1016/bs.apar.2023.12.002; 3) Özben et al. 2022, doi: 10.3390/pathogens11050490; 4) Jones et al. 2024 doi: 10.1186/s13071-024-06306-5; 5) Yilmaz et al. 2017, doi: 10.1016/j.ijpddr.2017.10.001; 6) Gerhard et al. 2020, doi: 10.1038/s41598-020-70529-6; 7) Gerhard et al. 2021, doi: 10.3390/ph14020153; 8) Janssen et al. 2013, doi: 10.1371/journal.pone.0061635.