UC Riverside

Cardiac glycosides (CGs) are toxic compounds produced or sequestered by certain plant and animal species for defense against enemies. CGs derive their toxicity to animals from inhibiting the Na+/K+-ATPase (NKA), a critical ion pump necessary for maintaining cell osmotic equilibrium and membrane potential. While some organisms that carry or otherwise encounter CGs evolved resistance through target site insensitivity (TSI) via substitutions in the NKA’s alpha subunit, others appear to have evolved alternative resistance mechanisms. For instance, milkweed herbivores such as the monarch butterfly and one of their natural enemies, the parasitic nematode Steinernema carpocapsae, exhibit TSI. However, the congener Steinernema feltiae shows partial CG resistance without some of the large-effect TSI substitutions, suggesting an alternative protective strategy. Likewise, some resistant insects, such as the milkweed tussock moth Euchaetes egle, lack TSI substitutions entirely. These observations point to the existence of possible additional CG resistance mechanisms, such as toxin efflux via ABC transporters or metabolic detoxification. Our study aims to uncover such alternative resistance mechanisms through studying wild isolates of Caenorhabditis elegans in the Caenorhabditis Natural Diversity Resource (CaeNDR). By conducting toxicity assays with ouabain, a model CG, we have identified resistant C. elegans strains. We are applying genome-wide association studies (GWAS) to determine genes and genetic variants linked to CG resistance. Our findings will shed light on the genetic architecture underlying CG resistance and emphasize the need to explore resistance mechanisms beyond TSI. Our research has broader implications for chemical ecology, evolutionary biology, and drug resistance studies.