A midgut transcriptional regulatory loop favors an insect host to withstand a bacterial pathogen

Mounting evidence suggests that insect hormones associated with growth and development also participate in pathogen defense. We have discovered a previously undescribed midgut transcriptional control pathway that modulates the availability of 20-hydroxyecdysone (20E) in a worldwide insect pest (Plutella xylostella), allowing it to defeat the major virulence factor of an insect pathogen Bacillus thuringiensis (Bt). A reduction of the transcriptional inhibitor (PxDfd) increases the expression of a midgut microRNA (miR-8545), which in turn represses the expression of a newly identified ecdysteroid-degrading glucose dehydrogenase (PxGLD). Downregulation of PxGLD reduces 20E degradation to increase 20E titer and concurrently triggers a transcriptional negative feedback loop to mitigate 20E overproduction. The moderately elevated 20E titer in the midgut activates a MAPK signaling pathway to increase Bt tolerance/resistance. These findings deepen our understanding of the functions attributed to these classical insect hormones and help inform potential future strategies that can be employed to control insect pests. [Display omitted] •Increased titer of the insect hormone 20-hydroxyecdysone (20E) facilitates an insect host, Plutella xylostella, to defeat its bacterial pathogen Bacillus thuringiensis (Bt).•Glucose dehydrogenase (GLD) was identified as a new insect ecdysone-degrading enzyme that can metabolize 20E.•A midgut miRNA initiated epigenetic regulatory pathway represses GLD activity and elevates 20E titer to resist the Bt pathogen.•An as-yet uncharacterized negative feedback loop reduces excess 20E to balance hormonal homeostasis.•This study provides new insights into the immunological landscape of classical insect hormones and the molecular basis of host-pathogen coevolution.