Staphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation

Staphylococcus aureus is a prominent human pathogen that readily adapts to host immune defenses. Here we show that, in contrast to Gram-negative pathogens, S. aureus induces a distinct airway immunometabolic response dominated by release of the electrophilic metabolite, itaconate. Itaconate inhibits S. aureus glycolysis and selects for strains that re-direct carbon flux to fuel extracellular polysaccharide (EPS) synthesis and biofilm formation. Itaconate-adapted strains, as illustrated by S. aureus isolates from chronic airway infection, exhibit decreased glycolytic activity, high EPS production, and proficient biofilm formation even before itaconate stimulation. S. aureus thus adapts to the itaconate-dominated immunometabolic response by producing biofilms, which are associated with chronic infection of the human airway.