UDP-glycosyltransferase family in Haemonchus contortus: Phylogenetic analysis, constitutive expression, sex-differences and resistance-related differences

Abstract

UDP-glycosyltransferases (UGT), catalysing conjugation of UDP-activated sugar donors to small lipophilic chemicals, are widespread in living organisms from bacteria to fungi, plant, or animals. The progress of genome sequencing has enabled an assessment of the UGT multigene family in Haemonchus contortus (family Trichostrongylidae, Nematoda), a hematophagous gastrointestinal parasite of small ruminants. Here we report 32 putative UGT genes divided into 15 UGT families. Phylogenetic analysis in comparison with UGTs from Caenorhabditis elegans, a free-living model nematode, revealed several single member homologues, a lack of the dramatic gene expansion seen in C. elegans, but also several families (UGT365, UGT366, UGT368) expanded in H. contortus only. The assessment of constitutive UGT mRNA expression in H. contortus adults identified significant differences between females and males. In addition, we compared the expression of selected UGTs in the drug-sensitive ISE strain to two benzimidazole-resistant strains, IRE and WR, with different genetic backgrounds. Constitutive expression of UGT368B2 was significantly higher in both resistant strains than in the sensitive strain. As resistant strains were able to deactivate benzimidazole anthelmintics via glycosylation more effectively then the sensitive strain, UGT368B2 enhanced constitutive expression might contribute to drug resistance in H. contortus.

Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

“…Although induced expression of certain DMEs in resistant isolates in comparison to sensitive ones has been reported repeatedly [5,6,12,14], the mechanisms and circumstances of this induction have not been elucidated. As the contact of nematodes with sub-lethal doses of anthelmintics may play an important role, we incubated ex vivo H. contortus adults from ISE strain (sensitive to all anthelmintics) with the anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO) at three sub-lethal doses for 4 and 12 h. Two different incubation duration were used because it is known that the time required to induce different DMEs differs significantly [29].…”

“…Thirty-two isoforms of UGTs, the most important Phase II enzymes catalyzing conjugation of UDP-activated sugar donors to small lipophilic chemicals, were identified in H. contortus genome. Constitutive expression of isoform UGT368B2 was significantly higher in H. contortus resistant strains than in the sensitive strains [12].…”

Transcriptional responses in Parascaris univalens after in vitro exposure to ivermectin, pyrantel citrate and thiabendazole

“…Although no consistent pattern was observed regardless of drug and concentration used, we found downregulation of several members of the phase II enzymes of the UGT family. In contrast, several studies have shown an increased expression and activity of UGTs in benzimidazole-resistant strains of H. contortus [29,63]. Although the expression and function of phase I and phase II enzymes have been investigated in parasitic helminths, few studies have focused on ascarid worms and thus further investigation is required.…”

A putative UDP-glycosyltransferase from Heterorhabditis bacteriophora suppresses antimicrobial peptide gene expression and factors related to ecdysone signaling

“…While this protein is larger than the predicted size, it is within Hb-ugt-1 a range that could be attributed to post-translational modification. Other helminths also produce multiple isoforms of UDP-glycosyltransferases 27 , which may be the case with H. bacteriophora and could alternatively explain the size discrepancy.…”