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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Citrobacter rodentium*/genetics ; Citrobacter rodentium*/pathogenicity ; Gene Expression Regulation, Bacterial* ; Enterohemorrhagic Escherichia coli*/pathogenicity ; Enterohemorrhagic Escherichia coli*/genetics ; Enterohemorrhagic Escherichia coli*/metabolism ; Virulence Factors*/genetics ; Virulence Factors*/metabolism ; Enterobacteriaceae Infections*/microbiology ; Enterobacteriaceae Infections*/metabolism ; Enterobacteriaceae Infections*/genetics; Animals ; Mice ; Virulence ; Humans ; Escherichia coli Proteins/metabolism ; Escherichia coli Proteins/genetics ; Escherichia coli Infections/microbiology ; Escherichia coli Infections/metabolism ; Carbon/metabolism ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Phosphoproteins/metabolism ; Phosphoproteins/genetics ; Bacterial Adhesion ; Bacterial Proteins/metabolism ; Bacterial Proteins/genetics

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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Wale et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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United Kingdom WT_ Wellcome Trust

0 (Virulence Factors)
0 (Escherichia coli Proteins)
7440-44-0 (Carbon)
0 (Transcription Factors)
0 (Phosphoproteins)
0 (LEE protein, E coli)
0 (Bacterial Proteins)

Date Created: 20241015 Date Completed: 20241025 Latest Revision: 20241027

20241027

PMC11508082

10.1371/journal.ppat.1012451

39405360