A master regulator of central carbon metabolism directly activates virulence gene expression in attaching and effacing pathogens

• Published in: PLoS pathogens 2024-10, Vol.20 (10), p.e1012451
• Main Authors: Wale, Kabo R, O'Boyle, Nicky, McHugh, Rebecca E, Serrano, Ester, Mark, David R, Douce, Gillian R, Connolly, James P R, Roe, Andrew J
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Bacterial Adhesion; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Carbon - metabolism; Cell adhesion; Citrobacter rodentium - genetics; Citrobacter rodentium - pathogenicity; Control; DNA binding proteins; Enterobacteriaceae Infections - genetics; Enterobacteriaceae Infections - metabolism; Enterobacteriaceae Infections - microbiology; Enterohemorrhagic Escherichia coli - genetics; Enterohemorrhagic Escherichia coli - metabolism; Enterohemorrhagic Escherichia coli - pathogenicity; Escherichia coli; Escherichia coli Infections - metabolism; Escherichia coli Infections - microbiology; Escherichia coli Proteins - genetics; Escherichia coli Proteins - metabolism; Gene Expression Regulation, Bacterial; Genetic aspects; Genetic research; Genetic transcription; Genomes; Genomics; Health aspects; Humans; Identification and classification; Mice; Pathogenic microorganisms; Phosphoproteins - genetics; Phosphoproteins - metabolism; Physiological aspects; Transcription Factors - genetics; Transcription Factors - metabolism; Virulence; Virulence (Microbiology); Virulence Factors - genetics; Virulence Factors - metabolism
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012451

The ability of the attaching and effacing pathogens enterohaemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium to overcome colonisation resistance is reliant on a type 3 secretion system used to intimately attach to the colonic epithelium. This crucial virulence factor is encoded on a pathogenicity island known as the Locus of Enterocyte Effacement (LEE) but its expression is regulated by several core-genome encoded transcription factors. Here, we unveil that the core transcription factor PdhR, traditionally known as a regulator of central metabolism in response to cellular pyruvate levels, is a key activator of the LEE. Through genetic and molecular analyses, we demonstrate that PdhR directly binds to a specific motif within the LEE master regulatory region, thus activating type 3 secretion directly and enhancing host cell adhesion. Deletion of pdhR in EHEC significantly impacted the transcription of hundreds of genes, with pathogenesis and protein secretion emerging as the most affected functional categories. Furthermore, in vivo studies using C. rodentium, a murine model for EHEC infection, revealed that PdhR is essential for effective host colonization and maximal LEE expression within the host. Our findings provide new insights into the complex regulatory networks governing bacterial pathogenesis. This research highlights the intricate relationship between virulence and metabolic processes in attaching and effacing pathogens, demonstrating how core transcriptional regulators can be co-opted to control virulence factor expression in tandem with the cell's essential metabolic circuitry.