Complementary Approaches with Free-living and Parasitic Nematodes to Understanding Anthelmintic Resistance

Wit, Janneke; Dilks, Clayton M.; Andersen, Erik C.

doi:10.1016/j.pt.2020.11.008

“…This study emphasizes that, although powerful, QTL mapping is ultimately a statistical method that can be influenced by experimental differences and that it is essential to validate QTL before drawing conclusions about the genomic location of the causal variant. Although validating QTL can be difficult in many parasitic nematode species, our ability to validate QTL in C. elegans is a strength of this model organism, emphasizing the need for the parasitic nematode and C. elegans communities to work together to push forward a cycle of discovery to understand anthelmintic modes of action and mechanisms of resistance [24].…”

Section: Different Mapping Populations and Techniques Detect Both Similar And Distinct Qtlmentioning

confidence: 99%

“…This study demonstrates the power of functional validation in model systems like C. elegans to experimentally test hypotheses for candidate genes with one-to-one orthologs. To study the resistance conferred by genes that have multiple orthologs in one or both species, genome-editing could be used to make C. elegans gene content resemble parasitic nematodes [24,61]. Additionally, CeNDR can be used to identify strains that have similar gene contents as found in H. contortus [42,62].…”

Section: Plos Pathogensmentioning

confidence: 99%

“…[15,23]. Finally, most species lack key molecular and genetic tools such as CRISPR-Cas9 genome editing [24]. By contrast, the free-living nematode C. elegans has a short life cycle that is easy to grow in the laboratory, a well annotated reference genome, and a plethora of molecular and genetic tools to characterize anthelmintic responses [20,21,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

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Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses

Evans

¹

,

Wit

²

,

Stevens

³

et al. 2021

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Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance for most of these drugs. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C. elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel (glc-1). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C. elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C. elegans as a model to better understand ML resistance in parasitic nematodes.

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“…This study demonstrates the power of functional validation in model systems like C. elegans to experimentally test hypotheses for candidate genes with one-to-one orthologs. To study the resistance conferred by genes that have multiple orthologs in one or both species, genome-editing could be used to make C. elegans gene content resemble parasitic nematodes[23,56].This study highlights the benefits of communication between the parasite and C. elegans communities. Genetic mappings, screens, and selections are more easily performed in free-living nematodes and ultimately discover drug targets and mechanisms of action.…”

mentioning

confidence: 92%

“…To date, the most complete genome is Haemonchus contortus, which enables genetic mappings and comparative genomic approaches [14,22]. Finally, most species lack key molecular and genetic tools such as CRISPR-Cas9 genome editing [23]. By contrast, the free-living nematode C. elegans has a short life cycle that is easy to grow in the laboratory, a well annotated reference genome, and a plethora of molecular and genetic tools to characterize anthelmintic responses [19,20,[24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Two novel loci underlie natural differences inCaenorhabditis elegansmacrocyclic lactone responses

Andersen

¹

,

Evans

²

,

Wit

³

et al. 2021

Preprint

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Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C. elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel (glc-1). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C. elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C. elegans as a model to better understand ML resistance in parasitic nematodes.Author SummaryParasitic nematodes infect plants, animals, and humans, causing major health and economic burdens worldwide. Parasitic nematode infections are generally treated efficiently with a class of drugs named anthelmintics. However, resistance to many of these anthelmintic drugs, including macrocyclic lactones (MLs), is rampant and increasing. Therefore, it is essential that we understand how these drugs act against parasitic nematodes and, conversely, how nematodes gain resistance in order to better treat these infections in the future. Here, we used the non-parasitic nematode Caenorhabditis elegans as a model organism to study ML resistance. We leveraged natural genetic variation between strains of C. elegans with differential responses to abamectin to identify three genomic regions on chromosome V, each containing one or more genes that contribute to ML resistance. Two of these loci have not been previously discovered and likely represent novel resistance mechanisms. We also compared the genes in these two novel loci to the genes found within genomic regions linked to ML resistance in the parasite Haemonchus contortus and found several cases of overlap between the two species. Overall, this study highlights the advantages of using C. elegans to understand anthelmintic resistance in parasitic nematodes.

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Anthelmintic resistance in soil-transmitted helminths: One-Health considerations

Ng’etich,

Amoah,

Bux

et al. 2023

Parasitol Res

10

0

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The One-Health approach recognizes the intricate connection between human, animal, and environmental health, and that cooperative effort from various professionals provides comprehensive awareness and potential solutions for issues relating to the health of people, animals, and the environment. This approach has increasingly gained appeal as the standard strategy for tackling emerging infectious diseases, most of which are zoonoses. Treatment with anthelmintics (AHs) without a doubt minimizes the severe consequences of soil-transmitted helminths (STHs); however, evidence of anthelmintic resistance (AR) development to different helminths of practically every animal species and the distinct groups of AHs is overwhelming globally. In this regard, the correlation between the application of anthelmintic drugs in both human and animal populations and the consequent development of anthelmintic resistance in STHs within the context of a One-Health framework is explored. This review provides an overview of the major human and animal STHs, treatment of the STHs, AR development and drug-related factors contributing towards AR, One-Health and STHs, and an outline of some One-Health strategies that may be used in combating AR.

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Complementary Approaches with Free-living and Parasitic Nematodes to Understanding Anthelmintic Resistance

Cited by 44 publications

References 86 publications

Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses

Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses

Two novel loci underlie natural differences inCaenorhabditis elegansmacrocyclic lactone responses

Anthelmintic resistance in soil-transmitted helminths: One-Health considerations

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