Abstract
Parasitic nematode infections cause an enormous global burden to both humans and livestock. Resistance to the limited arsenal of anthelmintic drugs used to combat these infections is widespread, including benzimidazole (BZ) compounds. Previous studies using the free-living nematode Caenorhabditis elegans to model parasitic nematode resistance have shown that loss-of-function mutations in the beta-tubulin gene ben-1 confer resistance to BZ drugs. However, the mechanism of resistance and the tissue-specific susceptibility are not well known in any nematode species. To identify in which tissue(s) ben-1 function underlies BZ susceptibility, transgenic strains that express ben-1 in different tissues, including hypodermis, muscles, neurons, intestine, and ubiquitous expression were generated. High-throughput fitness assays were performed to measure and compare the quantitative responses to BZ compounds among different transgenic lines. Significant BZ susceptibility was observed in animals expressing ben-1 in neurons, comparable to expression using the ben-1 promoter. This result suggests that ben-1 function in neurons underlies susceptibility to BZ. Subsetting neuronal expression of ben-1 based on the neurotransmitter system further restricted ben-1 function in cholinergic neurons to cause BZ susceptibility. These results better inform our current understanding of the cellular mode of action of BZs and also suggest additional treatments that might potentiate the effects of BZs in neurons.
Original language | English (US) |
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Pages (from-to) | 89-96 |
Number of pages | 8 |
Journal | International Journal for Parasitology: Drugs and Drug Resistance |
Volume | 20 |
DOIs | |
State | Published - Dec 2022 |
Funding
We would like to thank Clay Dilks, Katie Evans, and Nicole Banks for their help with experiments and analysis and Amanda Shaver for her helpful comments on this manuscript. This work was supported by the National Institutes of Health NIAID grant R01AI153088 to ECA. This study used data made available by the C. elegans Neuronal Gene Expression Map and Network (NIH NINDS R01NS100547). Neurotransmitter system data are from WormAtlas neurotransmitter tables by Curtis M. Loer and James B. Rand (Loer and Rand, 2010), compiled from (Pereira et al. 2015; Gendrel et al. 2016; Serrano-Saiz et al. 2017). Some diagrams in figures were created using BioRender.com. We would like to thank Clay Dilks, Katie Evans, and Nicole Banks for their help with experiments and analysis and Amanda Shaver for her helpful comments on this manuscript. This work was supported by the National Institutes of Health NIAID grant R01AI153088 to ECA. This study used data made available by the C. elegans Neuronal Gene Expression Map and Network ( NIH NINDS R01NS100547 ). Neurotransmitter system data are from WormAtlas neurotransmitter tables by Curtis M. Loer and James B. Rand ( Loer and Rand, 2010 ), compiled from ( Pereira et al., 2015 ; Gendrel et al., 2016 ; Serrano-Saiz et al., 2017 ). Some diagrams in figures were created using BioRender.com .
Keywords
- Benzimidazole resistance
- C.elegans
- High-throughput assay
ASJC Scopus subject areas
- Parasitology
- Infectious Diseases
- Pharmacology (medical)