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

Area of Science:

• Microbiology
• Immunology
• Host-pathogen interactions

Background:

• Disease tolerance limits host damage during infection without harming pathogens.
• Streptococcus pyogenes employs aerobic mixed-acid fermentation to modulate disease tolerance.
• Microbe-derived molecules mediating this host-pathogen communication are not well understood.

Purpose of the Study:

• To identify microbe-derived molecules involved in Streptococcus pyogenes-mediated disease tolerance.
• To investigate the impact of aerobic mixed-acid fermentation on host inflammatory responses.
• To evaluate therapeutic strategies targeting bacterial fermentation pathways.

Main Methods:

• Utilized a murine infection model.
• Analyzed inflammatory cell accumulation (neutrophils, macrophages).
• Measured cytokine expression (interleukin-10).
• Assessed bacterial clearance and wound healing.
• Investigated host acetyl-CoA metabolism.
• Employed a pyruvate dehydrogenase inhibitor.

Main Results:

• Aerobic mixed-acid fermentation by S. pyogenes inhibited inflammatory cell infiltration and reduced interleukin-10.
• Fermentation end-products acetate and formate upregulated host acetyl-CoA metabolism and decreased interleukin-10.
• Inhibition of fermentation via a pyruvate dehydrogenase inhibitor reduced tissue damage and increased interleukin-10.
• Delayed bacterial clearance and wound healing were observed during fermentation.

Conclusions:

• Reprogramming bacterial carbon metabolism, specifically aerobic mixed-acid fermentation, influences host disease tolerance pathways.
• Acetate and formate are key Streptococcus pyogenes-derived molecules that modulate host inflammatory responses.
• Targeting bacterial pyruvate dehydrogenase represents a potential therapeutic approach to mitigate infection-induced tissue damage.