Costs and consequences of insect immunity Imperial College London

Insect immune systems frequently rely on antimicrobial peptides as critical antimicrobial effectors. We have explored the consequences of this reliance by examining the interaction between Drosophila melanogaster and the ubiquitous broad host range pathogen Enterococcus faecalis. Remarkably, we have identified an Enterococcus surface protein that is specifically targeted by a Drosophila effector peptide; this biochemical interaction is required for immune antimicrobial activity. The identified target is a regulator of cell envelope stress responses that is frequently mutated in strains that acquire antimicrobial resistance in the clinic. Mutations in this target, or in several other stress-response systems that alter its expression, confer near-complete resistance to killing by the Drosophila immune response. All of these mutations also alter antimicrobial sensitivity; conversely, selection of Enterococcus faecalis with antimicrobials in vitro is sufficient to confer strong increases in virulence. We thus demonstrate a new mechanism by which host immunity can select antimicrobial resistance in the absence of antibiotic exposure.