Reprogramming aerobic metabolism mitigates Streptococcus pyogenes tissue damage in a mouse necrotizing skin infection model

Wei Xu, Tara R. Bradstreet, Zongsen Zou, Suzanne Hickerson, Yuan Zhou, Hongwu He, Brian T. Edelson and Michael G. Caparon ()
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Wei Xu: Washington University School of Medicine
Tara R. Bradstreet: Washington University School of Medicine
Zongsen Zou: Washington University School of Medicine
Suzanne Hickerson: Washington University School of Medicine
Yuan Zhou: Jiangxi Normal University
Hongwu He: Central China Normal University
Brian T. Edelson: Washington University School of Medicine
Michael G. Caparon: Washington University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Disease tolerance is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates disease tolerance using its aerobic mixed-acid fermentation pathway via the enzyme pyruvate dehydrogenase, but the microbe-derived molecules that mediate communication with the host’s disease tolerance pathways remain elusive. Here we show in a murine model that aerobic mixed-acid fermentation inhibits the accumulation of inflammatory cells including neutrophils and macrophages, reduces the immunosuppressive cytokine interleukin-10, and delays bacterial clearance and wound healing. In infected macrophages, the aerobic mixed-acid fermentation end-products acetate and formate from streptococcal upregulate host acetyl-CoA metabolism and reduce interleukin-10 expression. Inhibiting aerobic mixed-acid fermentation using a bacterial-specific pyruvate dehydrogenase inhibitor reduces tissue damage during murine infection, correlating with increased interleukin-10 expression. Our results thus suggest that reprogramming carbon flow provides a therapeutic strategy to mitigate tissue damage during infection.

Date: 2025
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DOI: 10.1038/s41467-025-57348-x

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