Reprogramming Short-Chain Fatty Acid Metabolism Mitigates Tissue Damage for Streptococcus pyogenes Necrotizing Skin...

Area of Science:

• Microbiology
• Immunology
• Biochemistry

Background:

• Disease Tolerance (DT) limits host damage during infection without harming pathogens.
• Streptococcus pyogenes manipulates DT via aerobic mixed-acid fermentation (ARMAF) and pyruvate dehydrogenase (PDH) to affect IL-10 expression.
• The specific microbial molecules mediating host communication in DT pathways are unknown.

Approach:

• Investigated how ARMAF impacts IL-10-producing inflammatory cells (neutrophils, macrophages).
• Identified acetate and formate as bacterial fermentation products that inhibit IL-10 expression.
• Examined the mechanism involving host acetyl-CoA metabolism and non-histone lysine acetylation.
• Tested a bacterial-specific PDH inhibitor in a murine infection model.

Key Points:

• ARMAF inhibits IL-10-producing inflammatory cells, delaying bacterial clearance and wound healing.
• Bacterial acetate and formate suppress IL-10 by altering host acetyl-CoA metabolism and lysine acetylation.
• Targeting bacterial carbon metabolism offers a strategy to reduce infection-induced tissue damage.

Conclusions:

• Streptococcus pyogenes utilizes ARMAF to suppress host inflammatory responses, promoting its survival at the cost of host tissue damage.
• Bacterial short-chain fatty acids (acetate, formate) are key mediators in this immune evasion strategy.
• Inhibiting bacterial pyruvate dehydrogenase presents a promising therapeutic avenue for mitigating tissue damage in S. pyogenes infections.