Staphylococcus aureus small colony variants impair host immunity by activating host cell glycolysis and inducing necroptosis

Nat Microbiol. 2020 Jan;5(1):141-153. doi: 10.1038/s41564-019-0597-0. Epub 2019 Nov 4.


Staphylococcus aureus small colony variants (SCVs) are frequently associated with chronic infection, yet they lack expression of many virulence determinants associated with the pathogenicity of wild-type strains. We found that both wild-type S. aureus and a ΔhemB SCV prototype potently activate glycolysis in host cells. Glycolysis and the generation of mitochondrial reactive oxygen species were sufficient to induce necroptosis, a caspase-independent mechanism of host cell death that failed to eradicate S. aureus and instead promoted ΔhemB SCV pathogenicity. To support ongoing glycolytic activity, the ΔhemB SCV induced over a 100-fold increase in the expression of fumC, which encodes an enzyme that catalyses the degradatin of fumarate, an inhibitor of glycolysis. Consistent with fumC-dependent depletion of local fumarate, the ΔhemB SCV failed to elicit trained immunity and protection from a secondary infectious challenge in the skin. The reliance of the S. aureus SCV population on glycolysis accounts for much of its role in the pathogenesis of S. aureus skin infection.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cells, Cultured
  • Fumarates / metabolism
  • Gene Expression Regulation, Bacterial
  • Glycolysis
  • Humans
  • Immune Evasion
  • Immunomodulation*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Necroptosis / genetics
  • Reactive Oxygen Species / metabolism
  • Staphylococcal Skin Infections / immunology
  • Staphylococcal Skin Infections / metabolism*
  • Staphylococcal Skin Infections / microbiology
  • Staphylococcal Skin Infections / pathology*
  • Staphylococcus aureus / genetics
  • Staphylococcus aureus / growth & development
  • Staphylococcus aureus / metabolism
  • Staphylococcus aureus / pathogenicity*
  • THP-1 Cells


  • Bacterial Proteins
  • Fumarates
  • Reactive Oxygen Species