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<p>Building on our finding that <i>Streptococcus pyogenes</i> pyruvate dehydrogenase (PDH) suppresses host disease tolerance (DT) via short-chain fatty acid (SCFA)-mediated modulation of host acetyl-CoA and IL-10 levels, we characterize the global transcriptomic and epigenetic mechanisms underlying this immunometabolic manipulation. Combining new histological and ultrastructural analyses with an in-depth re-analysis of single-cell and bulk RNA-seq datasets to more comprehensively characterize the DT response, we show that PDH deficiency is associated with broad immunologic rewiring, characterized by intracellular bacterial containment within phagocytes, expansion of pro-resolving myeloid cells, and altered cell–cell communication. Metabolic analysis of ΔPdh-infected tissues revealed a shift away from acetyl-CoA metabolism towards glycolysis and the coordinated activation of a multi-faceted DT program, encompassing hypoxia signaling, iron handling, and the NRF2-mediated antioxidant response. Crucially, a focused re-analysis of existing transcriptome datasets from Histone Deacetylase (HDAC)-inhibited macrophages suggested that Trichostatin A (TSA) abrogates the protective transcriptome in ΔPdh infection, indicating that acetylation-dependent repression functions as a key regulator of the host DT response. By integrating new experimental data with advanced computational analyses, our work reveals a bacterial strategy of metabolic-epigenetic crosstalk, suggesting acetylation as a critical control point for mitigating infection-associated tissue damage.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月4日

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  • Sumit Kumar Paudel,
  • Sowmya Gannavaram,
  • Michael G. Caparon,
  • Wei Xu

摘要

Building on our finding that Streptococcus pyogenes pyruvate dehydrogenase (PDH) suppresses host disease tolerance (DT) via short-chain fatty acid (SCFA)-mediated modulation of host acetyl-CoA and IL-10 levels, we characterize the global transcriptomic and epigenetic mechanisms underlying this immunometabolic manipulation. Combining new histological and ultrastructural analyses with an in-depth re-analysis of single-cell and bulk RNA-seq datasets to more comprehensively characterize the DT response, we show that PDH deficiency is associated with broad immunologic rewiring, characterized by intracellular bacterial containment within phagocytes, expansion of pro-resolving myeloid cells, and altered cell–cell communication. Metabolic analysis of ΔPdh-infected tissues revealed a shift away from acetyl-CoA metabolism towards glycolysis and the coordinated activation of a multi-faceted DT program, encompassing hypoxia signaling, iron handling, and the NRF2-mediated antioxidant response. Crucially, a focused re-analysis of existing transcriptome datasets from Histone Deacetylase (HDAC)-inhibited macrophages suggested that Trichostatin A (TSA) abrogates the protective transcriptome in ΔPdh infection, indicating that acetylation-dependent repression functions as a key regulator of the host DT response. By integrating new experimental data with advanced computational analyses, our work reveals a bacterial strategy of metabolic-epigenetic crosstalk, suggesting acetylation as a critical control point for mitigating infection-associated tissue damage.