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<p>Chronic infections by <i>Pseudomonas aeruginosa</i> in people with cystic fibrosis are characterized by persistent inflammation and oxidative stress, yet the mechanisms enabling bacterial persistence are not fully understood. Here, we identify a persistence mechanism mediated by pyruvate secretion resulting from mutations in the pyruvate dehydrogenase complex in clinical isolates of <i>P. aeruginosa</i>, with putative analogous mutations also identified in <i>Staphylococcus aureus</i>, <i>Haemophilus influenzae</i> and <i>Stenotrophomonas maltophilia</i>. These mutations lead to elevated extracellular pyruvate, which dampens host inflammatory responses and favors bacterial persistence. Pyruvate exerts multiple roles: scavenges reactive oxygen species such as H<sub>2</sub>O<sub>2</sub>, suppresses host immune activation both in airway epithelial cells and macrophages, and increases bacterial survival during phagocytosis. This metabolic crosstalk promotes bacterial persistence while reducing epithelial and macrophage inflammatory responses. Our findings reveal pyruvate as a bacterial immunometabolite that mimics host antioxidant defenses, reshaping the infection niche to favor long-term colonization. This work highlights the broader role of secreted metabolites in host-pathogen interactions and suggests new strategies targeting metabolic pathways to manage chronic infections.</p>

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Immune protection and persistence in Pseudomonas aeruginosa infections by pyruvate cross-feeding

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月8日

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  • Stefanos Lampadariou,
  • Pablo Laborda,
  • Lorenzo Masiero,
  • Søren Molin,
  • Helle Krogh Johansen,
  • Ruggero La Rosa

摘要

Chronic infections by Pseudomonas aeruginosa in people with cystic fibrosis are characterized by persistent inflammation and oxidative stress, yet the mechanisms enabling bacterial persistence are not fully understood. Here, we identify a persistence mechanism mediated by pyruvate secretion resulting from mutations in the pyruvate dehydrogenase complex in clinical isolates of P. aeruginosa, with putative analogous mutations also identified in Staphylococcus aureus, Haemophilus influenzae and Stenotrophomonas maltophilia. These mutations lead to elevated extracellular pyruvate, which dampens host inflammatory responses and favors bacterial persistence. Pyruvate exerts multiple roles: scavenges reactive oxygen species such as H2O2, suppresses host immune activation both in airway epithelial cells and macrophages, and increases bacterial survival during phagocytosis. This metabolic crosstalk promotes bacterial persistence while reducing epithelial and macrophage inflammatory responses. Our findings reveal pyruvate as a bacterial immunometabolite that mimics host antioxidant defenses, reshaping the infection niche to favor long-term colonization. This work highlights the broader role of secreted metabolites in host-pathogen interactions and suggests new strategies targeting metabolic pathways to manage chronic infections.