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Nat Microbiol. 2019 Nov 4. doi: 10.1038/s41564-019-0597-0. [Epub ahead of print]

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

Author information

1
Department of Pediatrics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
2
Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
3
Microbiological Diagnostic Unit Public Health Laboratory, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
4
Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia.
5
Department of Pediatrics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA. asp7@cumc.columbia.edu.

Abstract

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.

PMID:
31686028
DOI:
10.1038/s41564-019-0597-0

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