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

Nat Commun. 2021 Mar 3;12(1):1399. doi: 10.1038/s41467-021-21718-y.


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 the release of the electrophilic metabolite, itaconate. The itaconate synthetic enzyme, IRG1, is activated by host mitochondrial stress, which is induced by staphylococcal glycolysis. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Biofilms / growth & development
  • Bronchoalveolar Lavage Fluid
  • Carbohydrate Metabolism
  • Cystic Fibrosis / microbiology
  • Gene Expression Regulation, Bacterial
  • Glycolysis / drug effects
  • Glycolysis / physiology
  • Host-Pathogen Interactions / immunology
  • Host-Pathogen Interactions / physiology*
  • Humans
  • Hydro-Lyases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Pseudomonas Infections / immunology
  • Pseudomonas Infections / metabolism
  • Reactive Oxygen Species / metabolism
  • Sputum / microbiology
  • Staphylococcal Infections / immunology*
  • Staphylococcal Infections / metabolism
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / isolation & purification
  • Staphylococcus aureus / pathogenicity*
  • Staphylococcus aureus / physiology*
  • Stress, Physiological
  • Succinates / metabolism*
  • Succinates / pharmacology
  • Succinic Acid / metabolism
  • Young Adult


  • Reactive Oxygen Species
  • Succinates
  • Succinic Acid
  • Hydro-Lyases
  • Irg1 protein, mouse
  • itaconic acid