The Role of Host Hormones and Metabolites in the Regulation of Virulence in Enterohemorrhagic Escherichia coli (EHEC)
Njoroge, Jacqueline W.
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Gastrointestinal bacteria, including the enteric pathogen enterohemorrhagic Escherichia coli O157:H7 (EHEC) that causes hemorrhagic colitis, sense diverse environmental signals, and use them as cues for differential gene regulation and niche adaptation. This allows for a temporal and energy efficient up-regulation of EHEC virulence factors that is essential for successful colonization and infection of the host. These virulence factors include motility genes, Shiga toxin, and attaching and effacing (AE) lesion formation on colonic epithelial cells. AE lesion formation is primarily regulated by a pathogenicity island (PI) known as the locus of enterocyte effacement (LEE). One of the signals sensed by EHEC to activate virulence is the mammalian hormone epinephrine. We investigated the extent of epinephrine regulation in EHEC through transcriptome studies. The bacterial adrenergic kinases QseC and QseE both respond to epinephrine to regulate the LEE PI positively and negatively respectively. We also demonstrated for the first time that co-incubation with epinephrine increases the formation of AE lesions, and that QseC and QseE are the only sensors of epinephrine in EHEC. Epinephrine is not the only host hormone sensed by EHEC. We showed that another human hormone, serotonin is sensed by EHEC, Citrobacter rodentium and uropathogenic E.coli. In EHEC and C.rodentium we showed that serotonin inhibits the transcription of the LEE PI. We also determined that the mechanism of LEE PI inhibition by serotonin is through the reduction of autophosphorylation of the bacterial sensor kinase CpxA, which is itself an activator of the LEE PI. In addition to chemical signaling, nutrient availability plays an important role in bacterial gene regulation. We investigated the role that carbon nutrients play in the regulation of EHEC virulence. We showed that the LEE PI is activated under gluconeogenic conditions, which has been shown to be important for the maintenance of colonization in vivo, and inhibited under glycolytic conditions. We also identified a novel glucose concentration dependent regulator of the LEE PI, Cra. These findings enhanced our understanding of the role that epinephrine plays in virulence, and introduced two other signals, serotonin and glucose which are both important for the regulation of EHEC virulence genes.