Metabolomic investigation of host-cell responses to S. aureus SCV infection

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 a ?hemB SCV prototype potently activates glycolysis in host cells. Glycolysis and the generation of mitochondrial ROS were sufficient to induce necroptosis, a caspase-independent mechanism of host cell death that failed to eradicate S. aureus and instead perpetuated infection. To ensure ongoing glycolytic activity, the ?hemB SCV induced over 100-fold increase in fumC expression which degrades fumarate, a known glycolysis inhibitor. Consistent with fumC-dependent depletion of local fumarate, the ?hemB SCV failed to elicit trained immunity and protection from a secondary infectious challenge in the skin. The reliance of the S. aureus SCV population upon glycolysis accounts for much of its role in S. aureus pathogenesis.