Quantifying the fitness effects of resistance alleles with and without anthelmintic selection pressure using Caenorhabditis elegans .

Autor:	Shaver AO; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Miller IR; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Schaye ES; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Moya ND; Dept. of Biology, Johns Hopkins University, Baltimore, Maryland, United States of America., Collins JB; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Wit J; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Blanco AH; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Shao FM; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Andersen EJ; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Khan SA; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Paredes G; Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America., Andersen EC; Dept. of Biology, Johns Hopkins University, Baltimore, Maryland, United States of America.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 06. Date of Electronic Publication: 2024 Feb 06.
DOI:	10.1101/2024.02.01.578300
Abstrakt:	Albendazole and ivermectin are the two most commonly co-administered anthelmintic drugs in mass-drug administration programs worldwide. Despite emerging resistance, we do not fully understand the mechanisms of resistance to these drugs nor the consequences of delivering them in combination. Albendazole resistance has primarily been attributed to variation in the drug target, a beta-tubulin gene. Ivermectin targets glutamate-gated chloride channel (GluCl) genes, but it is unknown whether these genes are involved in ivermectin resistance in nature. Using Caenorhabditis elegans , we defined the fitness costs associated with loss of the drug target genes singly or in combinations of the genes that encode GluCl subunits. We quantified the loss-of function effects on three traits: (i) multi-generational competitive fitness, (ii) fecundity, and (iii) development. In competitive fitness and development assays, we found that a deletion of the beta-tubulin gene ben-1 conferred albendazole resistance, but ivermectin resistance required loss of two GluCl genes ( avr-14 and avr-15 ) or loss of three GluCl genes ( avr-14 , avr-15 , and glc-1 ). The fecundity assays revealed that loss of ben-1 did not provide any fitness benefit in albendazole and that no GluCl deletion mutants were resistant to ivermectin. Next, we searched for evidence of multi-drug resistance across the three traits. Loss of ben-1 did not confer resistance to ivermectin, nor did loss of any single GluCl subunit or combination confer resistance to albendazole. Finally, we assessed the development of 124 C. elegans wild strains across six benzimidazoles and seven macrocyclic lactones to identify evidence of multi-drug resistance between the two drug classes and found a strong phenotypic correlation within a drug class but not across drug classes. Because each gene affects various aspects of nematode physiology, these results suggest that it is necessary to assess multiple fitness traits to evaluate how each gene contributes to anthelmintic resistance. Competing Interests: COMPETING INTERESTS The authors have declared that no competing interests exist
Databáze:	MEDLINE
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