An acetylation-dependent switch underlies host disease tolerance during streptococcal infection

Area of Science:

• Immunometabolism
• Epigenetics
• Microbial Pathogenesis

Background:

• Streptococcus pyogenes pyruvate dehydrogenase (PDH) was previously found to suppress host disease tolerance (DT) by modulating short-chain fatty acid (SCFA)-mediated host acetyl-CoA and IL-10 levels.
• Understanding the transcriptomic and epigenetic mechanisms of this immunometabolic manipulation is crucial for deciphering host-pathogen interactions.

Purpose of the Study:

• To characterize the global transcriptomic and epigenetic mechanisms by which Streptococcus pyogenes PDH manipulates host disease tolerance.
• To investigate the role of metabolic reprogramming and epigenetic regulation in the host's response to bacterial infection.

Main Methods:

• Histological and ultrastructural analyses.
• Re-analysis of single-cell and bulk RNA-seq datasets.
• Metabolic analysis of infected tissues.
• Computational analysis of transcriptome datasets from HDAC-inhibited macrophages.

Main Results:

• PDH deficiency in S. pyogenes led to broad immunologic rewiring, including intracellular bacterial containment, myeloid cell expansion, and altered cell-cell communication.
• Infection induced a metabolic shift from acetyl-CoA metabolism to glycolysis, activating hypoxia signaling, iron handling, and NRF2-mediated antioxidant responses.
• Histone deacetylase (HDAC) inhibition abrogated the protective transcriptome, indicating acetylation-dependent repression regulates the host DT response.

Conclusions:

• Bacterial PDH employs a metabolic-epigenetic crosstalk strategy to manipulate host disease tolerance.
• Acetylation is identified as a critical control point for mitigating infection-associated tissue damage, offering potential therapeutic targets.