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Transcriptional Activator GmrA, Encoded in Genomic Island OI-29, Controls the Motility of Enterohemorrhagic Escherichia coli O157:H7.

ABSTRACT: Enterohemorrhagic Escherichia coli O157:H7 is a major human enteric pathogen capable of causing large outbreaks of severe infections that induce bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Its genome contains 177 unique O islands (OIs) including those carrying the main virulence elements, Shiga toxin-converting phages (OI-45 and OI-93) and locus for enterocyte effacement (OI-148). However, many of these islands harbor only genes of unknown function. Here, we demonstrate that OI-29 encodes a newly discovered transcriptional activator, Z0639 (named GmrA), that is required for motility and flagellar synthesis in O157:H7. GmrA directly binds to the promoter of fliA, an RNA polymerase sigma factor, and thereby regulates flagellar genes controlled by FliA. Expression of gmrA is maximal under host conditions (37°C, neutral pH, and physiological osmolarity), and in the presence of host epithelial cells, indicative of a role of this gene in infection by promoting motility. Finally, GmrA was found to be a widespread regulator of bacterial motility and flagellar synthesis in different pathotypes of E. coli. Our work largely enriches our understanding of bacterial motility control, and provides another example of regulators acquired laterally that mediate flagellar synthesis.

SUBMITTER: Yang B

PROVIDER: S-EPMC5826968 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The large intestinal pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7 detects host cues to regulate virulence gene expression during colonization and infection. However, virulence regulatory mechanisms of EHEC O157:H7 in the human large intestine are not fully understood. Herein, we identified a virulence-regulating pathway where the PhoQ/PhoP two-component regulatory system senses low magnesium levels and signals to the O island 119-encoded Z4267 (LmiA; low magnesium-induced regulator A), directly activating loci of enterocyte effacement genes to promote EHEC O157:H7 adherence in the large intestine. Disruption of this pathway significantly decreased EHEC O157:H7 adherence in the mouse intestinal tract. Moreover, feeding mice a magnesium-rich diet significantly reduced EHEC O157:H7 adherence in vivo This LmiA-mediated virulence regulatory pathway is also conserved among several EHEC and enteropathogenic E. coli serotypes; therefore, our findings support the use of magnesium as a dietary supplement and provide greater insights into the dietary cues that can prevent enteric infections.IMPORTANCE Sensing specific gut metabolites is an important strategy for inducing crucial virulence programs by enterohemorrhagic Escherichia coli (EHEC) O157:H7 during colonization and infection. Here, we identified a virulence-regulating pathway wherein the PhoQ/PhoP two-component regulatory system signals to the O island 119-encoded low magnesium-induced regulator A (LmiA), which, in turn, activates locus of enterocyte effacement (LEE) genes to promote EHEC O157:H7 adherence in the low-magnesium conditions of the large intestine. This regulatory pathway is widely present in a range of EHEC and enteropathogenic E. coli (EPEC) serotypes. Disruption of this pathway significantly decreased EHEC O157:H7 adherence in the mouse intestinal tract. Moreover, mice fed a magnesium-rich diet showed significantly reduced EHEC O157:H7 adherence in vivo, indicating that magnesium may help in preventing EHEC and EPEC infection in humans.

Project description:UNLABELLED:Bacterial pathogens must be able to both recognize suitable niches within the host for colonization and successfully compete with commensal flora for nutrients in order to establish infection. Ethanolamine (EA) is a major component of mammalian and bacterial membranes and is used by pathogens as a carbon and/or nitrogen source in the gastrointestinal tract. The deadly human pathogen enterohemorrhagic Escherichia coli O157:H7 (EHEC) uses EA in the intestine as a nitrogen source as a competitive advantage for colonization over the microbial flora. Here we show that EA is not only important for nitrogen metabolism but that it is also used as a signaling molecule in cell-to-cell signaling to activate virulence gene expression in EHEC. EA in concentrations that cannot promote growth as a nitrogen source can activate expression of EHEC's repertoire of virulence genes. The EutR transcription factor, known to be the receptor of EA, is only partially responsible for this regulation, suggesting that yet another EA receptor exists. This important link of EA with metabolism, cell-to-cell signaling, and pathogenesis, highlights the fact that a fundamental means of communication within microbial communities relies on energy production and processing of metabolites. Here we show for the first time that bacterial pathogens not only exploit EA as a metabolite but also coopt EA as a signaling molecule to recognize the gastrointestinal environment and promote virulence expression. IMPORTANCE:In order to successfully cause disease, a pathogen must be able to sense a host environment and modulate expression of its virulence genes as well as compete with the indigenous microbiota for nutrients. Ethanolamine (EA) is present in the large intestine due to the turnover of intestinal cells. Here, we show that the human pathogen Escherichia coli O157:H7, which causes bloody diarrhea and hemolytic-uremic syndrome, regulates virulence gene expression through EA metabolism and by responding to EA as a signal. These findings provide the first information directly linking EA with bacterial pathogenesis.

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Transcriptional Activator GmrA, Encoded in Genomic Island OI-29, Controls the Motility of Enterohemorrhagic Escherichia coli O157:H7.

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