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

Wong Fok Lung, Tania; Monk, Ian R.; Acker, Karen P.; Mu, Andre; Wang, Nancy; Riquelme Colet, Sebastian Alejandro; Pires, Silvia; Noguera, Loreani P.; Dach, Felix; Gabryszewski, Stanislaw J.; Howden, Benjamin P.; Prince, Alice S.

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.


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Nature Microbiology

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February 10, 2021