Catabolism of serine enantiomers represses enterohemorrhagic Escherichia coli virulence factors via modulation of the nitrogen stress response

• 成果类型: Article
• 署名作者: Addington, Emily; Wale, Kabo R.; Horsburgh, Emily; Fargeas, Margot; Spathis, Leonidas; Lesniak, Weronika; Flavin, Saoirse; Rimbi, Patricia T.; Mark, David R.; Sandalli, Sofia; Serrano, Ester; Blackburn, Gavin; Regnault, Clement; Whitfield, Phillip D.; Connolly, James P. R.; Roe, Andrew J.; O'boyle, Nicky
• 署名单位: University of Glasgow; University of Botswana; Trinity College Dublin; University of Glasgow; Newcastle University - UK
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2532916123
• 发表日期: 2026-03-18
• 页码: e2532916123
• 关键词: Escherichia coli; nitrogen metabolism; EHEC; type 3 secretion system; virulence; MURINE URINARY-TRACT; cell-wall; CONTROLS EXPRESSION; hydrogen-peroxide; SOS RESPONSE; locus; induction

摘要

Attaching and effacing pathogens, including enterohemorrhagic Escherichia coli (EHEC), colonize their preferred intestinal niche by sensing diverse host-, diet-, and microbiota-derived signals and coordinating the expression of virulence factors. D-serine, a host metabolite abundant in urine but scarce in the intestine, restricts EHEC colonization by transcriptionally repressing the type 3 secretion system (T3SS) while activating the SOS stress response. However, the mechanism underlying virulence regulation by D-serine remains unestablished. Here, we show that multiple amino acids, including L-serine converge on this pathway, repressing the T3SS without inducing the SOS response. Transcriptomic analyses showed a common response to D-and L-serine dominated by repression of nitrogen stress response genes. Mutational analysis identified the response regulators NtrC and Nac as essential mediators of T3SS repression by both serine enantiomers. Disruption of L-serine deaminase enzymes crucially revealed that T3SS repression depends on cytoplasmic ammonia/ammonium release rather than sensing of intact serine. While EHEC lacks canonical D-serine catabolic capacity, through metabolomics we provide evidence of oxidative deamination activity, capable of producing this regulatory signal. Together, these findings establish a mechanistic link between amino acid catabolism, nitrogen stress signaling, and virulence regulation in EHEC, highlighting how metabolic flux fine-tunes pathogen adaptation to intestinal niches.