The molecular mechanisms mediating a trade-off between insecticide resistance and development in an invasive pest

The evolution of insecticide resistance represents a global challenge to human food security and health. Resistance is often associated with fitness costs such as altered development and reproduction, however, the molecular mechanisms that underpin this evolutionary trade-off are poorly understood. Here we reveal the regulatory pathways underlying the trade-off between insecticide resistance and developmental regulation in the global invasive moth, Cydia pomonella. Using multi-omics approaches in combination with gene editing and transgenic approaches we show that overexpression of the glutathione S-transferase CpGSTd1 confers resistance to the pyrethroid insecticide λ-cyhalothrin. Computational alanine scanning (CAS), and site-specific mutagenesis reveal that the amino acid Tyr114 is a key structure-function determinant of CpGSTd1 metabolism of λ-cyhalothrin. CpGSTd1 is positively regulated by the transcription factor CpCncC, which is overexpressed in resistant C. pomonella, following its activation by reactive oxygen species (ROS). However, overexpression of CpCncC also promotes increased expression of the ecdysteroid biosynthesis gene CYP306A1, leading to elevated 20-hydroxyecdysone (20E) levels. Elevated 20E antagonized juvenile hormone (JH) synthesis, results in extended developmental durations and diminished reproductive capacity in resistant populations. Collectively, these findings provide insight into the molecular mechanisms underpinning insecticide resistance and highlight the role of transcription factors like CncC in mediating the trade-off between resistance and developmental homeostasis via their role as master regulators of genes involved in xenobiotic detoxification and hormonal pathways in insects.