Variation in anthelmintic responses are driven by genetic differences among diverse C. elegans wild strains

Area of Science:

• Parasitology
• Genetics
• Drug Discovery

Background:

• Anthelmintic drugs are crucial for treating parasitic nematode infections but face increasing resistance.
• The molecular and genetic basis of anthelmintic resistance (AR) is poorly understood for most drugs.
• Caenorhabditis elegans is a valuable model organism for studying AR due to its genetic tractability.

Purpose of the Study:

• To investigate genetic variation in anthelmintic responses using diverse Caenorhabditis elegans strains.
• To identify anthelmintics that exhibit population-wide genetic differences in efficacy.
• To determine the heritability of anthelmintic response variation and guide future AR gene discovery.

Main Methods:

• Conducted dose-response analyses of 26 anthelmintic drugs across genetically diverse C. elegans strains.
• Compared effective concentration (EC10) and slope estimates to a reference strain to identify genetic contributions to AR.
• Quantified heritability of anthelmintic response variation for each drug.

Main Results:

• C. elegans strains showed consistent responses within drug classes but significant variation across drug classes.
• Differential susceptibilities across strains and drugs were observed, highlighting C. elegans as a model for nematicide screening.
• A correlation was found between exposure near EC10 and high heritability of response, suggesting priority drugs for genetic studies.

Conclusions:

• Genetically diverse C. elegans strains are effective for dissecting the genetic basis of anthelmintic resistance.
• This study provides a framework for prioritizing drugs and genes for future genome-wide association studies to combat AR.
• Findings support the use of C. elegans as a model for screening novel nematicides and understanding AR mechanisms.