Altered avr-14B gene transcription patterns in ivermectin-resistant isolates of the cattle parasites, Cooperia oncophora and Ostertagia ostertagi

El-Abdellati, Abdelkarim; Graef, Jessie De; Zeveren, Annelies Van; Donnan, Alison; Skuce, Philip; Walsh, Tom; Wolstenholme, Adrian J.; Tait, Andy; Vercruysse, Jozef; Claerebout, Edwin; Geldhof, Peter

doi:10.1016/j.ijpara.2011.04.003

Cited by 41 publications

(28 citation statements)

References 27 publications

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“…It is reported that a single mutation in avr-14 does not confer notable resistance to ivermectin, whereas an avr-14 double mutant with avr-15 (a glutamate gated chloride ion channel on muscle cells) and triple mutant with avr-15 and glc-1 were significantly highly resistant to ivermectin [56]. In addition, avr-14 is conserved in parasitic nematodes [56, 60–62] whereas avr-15 is not [56]. …”

Section: Discussionmentioning

confidence: 99%

Nitazoxanide: Nematicidal mode of action and drug combination studies

Somvanshi

Ellis

et al. 2014

Molecular and Biochemical Parasitology

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Intestinal nematodes or roundworms (aka soil-transmitted helminths or STHs) cause great disease. They infect upwards of two billion people, leading to high morbidity and a range of health problems, especially in infected children and pregnant women. Development of resistance to the two main classes of drugs used to treat intestinal nematode infections of humans has been reported. To fight STH infections, we need new and more effective drugs and ways to improve the efficacy of the old drugs. One promising alternative drug is nitazoxanide (NTZ). NTZ, approved for treating human protozoan infections, was serendipitously shown to have therapeutic activity against STHs. However, its mechanism of action against nematodes is not known. Using the laboratory nematode Caenorhabditis elegans, we show that NTZ acts on the nematodes through avr-14, an alpha-type subunit of a glutamate-gated chloride ion channel known for its role in ivermectin susceptibility. In addition, a forward genetic screen to select C. elegans mutants resistant to NTZ resulted in isolation of two NTZ resistant mutants that are not in avr-14, suggesting that additional mechanisms are involved in resistance to NTZ. We found that NTZ combines synergistically with other classes of anthelmintic drugs, i.e. albendazole and pyrantel, making it a good candidate for further studies on its use in drug combination therapy of STH infections. Given NTZ acts against a wide range of nematode parasites, our findings also validate avr-14 as an excellent target for pan-STH therapy.

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Section: Discussionmentioning

confidence: 99%

Nitazoxanide: Nematicidal mode of action and drug combination studies

Somvanshi

Ellis

et al. 2014

Molecular and Biochemical Parasitology

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“…In Cooperia oncophora , an avr-14b allele encoding a L256F substitution confers two-to-three fold resistance (Njue et al, 2004). While this allele was present at a higher frequency in one IVM-resistant isolate compared with one sensitive isolate of C. oncophora (Njue and Prichard, 2004), it was not found in three other IVM-resistant isolates, although lower allelic diversity was observed at this locus relative to a susceptible isolate (El-Abdellati et al, 2011). In H. contortus , a T300S substitution in AVR-14B has been reported in the ML-resistant White River Strain (WRS), but no channels were formed by the expression of Hc-avr-14b T300S in Xenopus oocytes and the mutation had no effect on IVM binding (McCavera et al, 2009).…”

Section: Introductionmentioning

confidence: 92%

Analysis of putative resistance gene loci in UK field populations of Haemonchus contortus after 6 years of macrocyclic lactone use

Laing

Maitland

Lecová

et al. 2016

International Journal for Parasitology

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“…Although diverse molecules have been identified as targets of avermectins(3), only a few studies have examined natural resistance, with glutamate-gated chloride channels implicated in some(21,22) but not others(23,24). We have identified a naturally occurring four amino-acid deletion in the ligand-binding domain of GLC-1 that plays a major role in avermectin resistance in the global C. elegans population.…”

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confidence: 99%

Natural Variation in a Chloride Channel Subunit Confers Avermectin Resistance in C. elegans

Ghosh

Andersen

Shapiro

et al. 2012

Science

168

193

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Resistance of nematodes to anthelmintics such as avermectins has emerged as a major global health and agricultural problem, but genes conferring natural resistance to avermectins are unknown. We show that a naturally occurring four amino-acid deletion in the ligand-binding domain of GLC-1, the alpha-subunit of a glutamate-gated chloride channel, confers resistance to avermectins in the model nematode Caenorhabditis elegans. We also find that the same variant confers resistance to the avermectin-producing bacterium Streptomyces avermitilis. Population-genetic analyses identified two highly divergent haplotypes at the glc-1 locus that have been maintained at intermediate frequencies by long-term balancing selection. These results implicate variation in glutamate-gated chloride channels in avermectin resistance and provide a mechanism by which such resistance can be maintained.

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Altered avr-14B gene transcription patterns in ivermectin-resistant isolates of the cattle parasites, Cooperia oncophora and Ostertagia ostertagi

Cited by 41 publications

References 27 publications

Nitazoxanide: Nematicidal mode of action and drug combination studies

Nitazoxanide: Nematicidal mode of action and drug combination studies

Analysis of putative resistance gene loci in UK field populations of Haemonchus contortus after 6 years of macrocyclic lactone use

Natural Variation in a Chloride Channel Subunit Confers Avermectin Resistance in C. elegans

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