In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 3 ( 2023-3-2), p. e1011146-
Abstract:
Ancylostoma caninum is an important zoonotic gastrointestinal nematode of dogs worldwide and a close relative of human hookworms. We recently reported that racing greyhound dogs in the USA are infected with A . caninum that are commonly resistant to multiple anthelmintics. Benzimidazole resistance in A . caninum in greyhounds was associated with a high frequency of the canonical F167Y(T T C 〉 T A C) isotype-1 β-tubulin mutation. In this work, we show that benzimidazole resistance is remarkably widespread in A . caninum from domestic dogs across the USA. First, we identified and showed the functional significance of a novel benzimidazole isotype-1 β-tubulin resistance mutation, Q134H(CA A 〉 CA T ). Several benzimidazole resistant A . caninum isolates from greyhounds with a low frequency of the F167Y(T T C 〉 T A C) mutation had a high frequency of a Q134H(CA A 〉 CA T ) mutation not previously reported from any eukaryotic pathogen in the field. Structural modeling predicted that the Q134 residue is directly involved in benzimidazole drug binding and that the 134H substitution would significantly reduce binding affinity. Introduction of the Q134H substitution into the C . elegans β-tubulin gene ben-1 , by CRISPR-Cas9 editing, conferred similar levels of resistance as a ben-1 null allele. Deep amplicon sequencing on A . caninum eggs from 685 hookworm positive pet dog fecal samples revealed that both mutations were widespread across the USA, with prevalences of 49.7% (overall mean frequency 54.0%) and 31.1% (overall mean frequency 16.4%) for F167Y(T T C 〉 T A C) and Q134H(CA A 〉 CA T ), respectively. Canonical codon 198 and 200 benzimidazole resistance mutations were absent. The F167Y(T T C 〉 T A C) mutation had a significantly higher prevalence and frequency in Western USA than in other regions, which we hypothesize is due to differences in refugia. This work has important implications for companion animal parasite control and the potential emergence of drug resistance in human hookworms.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011146
DOI:
10.1371/journal.ppat.1011146.g001
DOI:
10.1371/journal.ppat.1011146.g002
DOI:
10.1371/journal.ppat.1011146.g003
DOI:
10.1371/journal.ppat.1011146.g004
DOI:
10.1371/journal.ppat.1011146.g005
DOI:
10.1371/journal.ppat.1011146.g006
DOI:
10.1371/journal.ppat.1011146.t001
DOI:
10.1371/journal.ppat.1011146.t002
DOI:
10.1371/journal.ppat.1011146.s001
DOI:
10.1371/journal.ppat.1011146.s002
DOI:
10.1371/journal.ppat.1011146.s003
DOI:
10.1371/journal.ppat.1011146.s004
DOI:
10.1371/journal.ppat.1011146.s005
DOI:
10.1371/journal.ppat.1011146.s006
DOI:
10.1371/journal.ppat.1011146.s007
DOI:
10.1371/journal.ppat.1011146.s008
DOI:
10.1371/journal.ppat.1011146.s009
DOI:
10.1371/journal.ppat.1011146.s010
DOI:
10.1371/journal.ppat.1011146.s011
DOI:
10.1371/journal.ppat.1011146.s012
DOI:
10.1371/journal.ppat.1011146.s013
DOI:
10.1371/journal.ppat.1011146.s014
DOI:
10.1371/journal.ppat.1011146.r001
DOI:
10.1371/journal.ppat.1011146.r002
DOI:
10.1371/journal.ppat.1011146.r003
DOI:
10.1371/journal.ppat.1011146.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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