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Lookup NU author(s): Dr James ConnollyORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright © 2026 the Author(s).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.
Author(s): Addington E, Wale KR, Horsburgh E, Fargeas M, Spathis L, Lesniak W, Flavin S, Rimbi PT, Mark DR, Sandalli S, Serrano E, Blackburn G, Regnault C, Whitfield PD, Connolly JPR, Roe AJ, O'Boyle N
Publication type: Article
Publication status: Published
Journal: Proceedings of the National Academy of Sciences of the United States of America
Year: 2026
Volume: 123
Issue: 12
Print publication date: 24/03/2026
Online publication date: 18/03/2026
Acceptance date: 19/02/2026
Date deposited: 14/04/2026
ISSN (print): 0027-8424
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: https://doi.org/10.1073/pnas.2532916123
DOI: 10.1073/pnas.2532916123
Data Access Statement: RNA sequencing data have been deposited at The European Nucleotide Archive [PRJEB101298 (64) and PRJEB89299 (65)]. The empty pSS XylS/Pm vector sequence has been deposited at NCBI (PX119074) (66). Study data are included in the article and/or supporting information. https://www.pnas.org/lookup/doi/10.1073/pnas.2532916123#supplementary-materials
PubMed id: 41849392
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