The Central Metabolism Regulator EIIA Glc Switches Salmonella from Growth Arrest to Acute Virulence through Activation of Virulence Factor Secretion

Mazé, Alain; Glatter, Timo; Bumann, Dirk

doi:10.1016/j.celrep.2014.04.022

Cited by 26 publications

(20 citation statements)

References 41 publications

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“…PTSs have been implicated in control of virulence in several additional Gram-negative and Gram-positive pathogens (23,50,51). Notably, at least in some cases, similar to our findings in V. cholerae, PTSs have been found to regulate the expression/activity of critical virulence regulators, e.g., Mga in Streptococcus pyogenes (52) and PrfA in Listeria monocytogenes (53), through various mechanisms.…”

Section: Discussionsupporting

confidence: 71%

A Genome-Wide Screen Reveals that the Vibrio cholerae Phosphoenolpyruvate Phosphotransferase System Modulates Virulence Gene Expression

et al. 2015

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dDiverse environmental stimuli and a complex network of regulatory factors are known to modulate expression of Vibrio cholerae's principal virulence factors. However, there is relatively little known about how metabolic factors impinge upon the pathogen's well-characterized cascade of transcription factors that induce expression of cholera toxin and the toxin-coregulated pilus (TCP). Here, we used a transposon insertion site (TIS) sequencing-based strategy to identify new factors required for expression of tcpA, which encodes the major subunit of TCP, the organism's chief intestinal colonization factor. Besides identifying most of the genes known to modulate tcpA expression, the screen yielded ptsI and ptsH, which encode the enzyme I (EI) and Hpr components of the V. cholerae phosphoenolpyruvate phosphotransferase system (PTS). In addition to reduced expression of TcpA, strains lacking EI, Hpr, or the associated EIIA Glc protein produced less cholera toxin (CT) and had a diminished capacity to colonize the infant mouse intestine. The PTS modulates virulence gene expression by regulating expression of tcpPH and aphAB, which themselves control expression of toxT, the central activator of virulence gene expression. One mechanism by which PTS promotes virulence gene expression appears to be by modulating the amounts of intracellular cyclic AMP (cAMP). Our findings reveal that the V. cholerae PTS is an additional modulator of the ToxT regulon and demonstrate the potency of loss-of-function TIS sequencing screens for defining regulatory networks. C holera remains a threat to public health in many parts of the world (1). This severe and sometimes lethal dehydrating diarrheal disease is caused by Vibrio cholerae, a curved Gram-negative rod. The El Tor biotype of V. cholerae is the cause of the ongoing seventh pandemic of cholera. Humans develop cholera after ingestion of water or food contaminated with the pathogen. Following ingestion, V. cholerae colonizes the small intestine where the bacteria produce cholera toxin (CT), an AB5 type toxin that induces a marked secretory response by enterocytes that accounts for the diarrhea characteristic of cholera. The toxin-coregulated pilus (TCP), a bundle-forming pilus whose production is coregulated with cholera toxin (2), is the chief V. cholerae colonization factor. The pilus enables V. cholerae microcolony formation in the intestine and may also promote adhesion to enterocytes (3).Extensive in vitro and in vivo studies have revealed that sophisticated regulatory processes control V. cholerae virulence gene expression (schematized in Fig. 1A) (reviewed in reference 4). Environmental signals trigger a virulence regulatory cascade, mediated by the membrane-imbedded proteins ToxR and TcpP/TcpH, that ultimately leads ToxT, an AraC-type transcription factor (5, 6), to directly activate the transcription of the genes encoding cholera toxin (ctxAB), TCP biogenesis, and several accessory colonization factors. ToxR can also directly activate ctxAB expression. Transcription of tcpPH re...

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Section: Discussionsupporting

confidence: 71%

A Genome-Wide Screen Reveals that the Vibrio cholerae Phosphoenolpyruvate Phosphotransferase System Modulates Virulence Gene Expression

et al. 2015

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“…Mutation of early components of the PTS (like EI), however, can have pleiotropic effects in the cell by altering EIIA Glc dependent control of adenylate cyclase activity and, therefore, the activity of the global regulator CRP (Deutscher et al ., ). EIIA Glc can also exert regulatory affects independent of CRP (Mazé et al ., ). Thus, it is difficult to uncouple the effect of an EI mutation on PTS‐dependent transport from its regulatory effect in the cell.…”

Section: Resultsmentioning

confidence: 97%

Systematic genetic dissection of PTS in Vibrio cholerae uncovers a novel glucose transporter and a limited role for PTS during infection of a mammalian host

Hayes

Dalia

2017

Molecular Microbiology

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A common mechanism for high affinity carbohydrate uptake in microbial species is the phosphoenolpyruvate-dependent phosphotransferase system (PTS). This system consists of a shared component, EI, which is required for all PTS transport, and numerous carbohydrate uptake transporters. In V. cholerae, there are 13 distinct PTS transporters. Due to genetic redundancy within this system, the carbohydrate specificity of each of these transporters is not currently defined. Here, using multiplex genome editing by natural transformation (MuGENT), we systematically dissect PTS transport in V. cholerae. Specifically, we generated a mutant strain that lacks all 13 PTS transporters, and from this strain, we created a panel of mutants where each expresses a single transporter. Using this panel, we have largely defined the carbohydrate specificities of each PTS transporter. Additionally, this analysis uncovered a novel glucose transporter. We have further defined the mechanism of this transporter and characterized its regulation. Using our 13 PTS transporter mutant, we also provide the first clear evidence that carbohydrate transport by the PTS is not essential during infection in an infant mouse model of cholera. In summary, this study shows how multiplex genome editing can be used to rapidly dissect complex biological systems and genetic redundancy in microbial systems.

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“…The activity of the Vibrio insulin-degrading enzyme in V. vulnificus is stimulated by dephosphorylated EIIA glc (18). EIIA glc also binds to the ATPase specific for T3SS-2 of Salmonella enterica, but this binding occurs in a phosphorylation-independent manner (17).…”

Section: Discussionmentioning

confidence: 99%

Glucose-Specific Enzyme IIA of the Phosphoenolpyruvate:Carbohydrate Phosphotransferase System Modulates Chitin Signaling Pathways in Vibrio cholerae

Yamamoto

Ohnishi

2017

J Bacteriol

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In Vibrio cholerae, the genes required for chitin utilization and natural competence are governed by the chitin-responsive two-component system (TCS) sensor kinase ChiS. In the classical TCS paradigm, a sensor kinase specifically phosphorylates a cognate response regulator to activate gene expression. However, our previous genetic study suggested that ChiS stimulates the non-TCS transcriptional regulator TfoS by using mechanisms distinct from classical phosphorylation reactions (S. Yamamoto, J. Mitobe, T. Ishikawa, S. N. Wai, M. Ohnishi, H. Watanabe, and H. Izumiya, Mol Microbiol 91:326 -347, 2014, https://doi.org/10.1111/mmi.12462). TfoS specifically activates the transcription of tfoR, encoding a small regulatory RNA essential for competence gene expression. Whether ChiS and TfoS interact directly remains unknown. To determine if other factors mediate the communication between ChiS and TfoS, we isolated transposon mutants that turned off tfoR::lacZ expression but possessed intact chiS and tfoS genes. We demonstrated an unexpected association of chitin-induced signaling pathways with the glucose-specific enzyme IIA (EIIA glc ) of the phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS) for carbohydrate uptake and catabolite control of gene expression. Genetic and physiological analyses revealed that dephosphorylated EIIA glc inactivated natural competence and tfoR transcription. Chitin-induced expression of the chb operon, which is required for chitin transport and catabolism, was also repressed by dephosphorylated EIIA glc . Furthermore, the regulation of tfoR and chb expression by EIIA glc was dependent on ChiS and intracellular levels of ChiS were not affected by disruption of the gene encoding EIIA glc . These results define a previously unknown connection between the PTS and chitin signaling pathways in V. cholerae and suggest a strategy whereby this bacterium can physiologically adapt to the existing nutrient status. IMPORTANCEThe EIIA glc protein of the PTS coordinates a wide variety of physiological functions with carbon availability. In this report, we describe an unexpected association of chitin-activated signaling pathways in V. cholerae with EIIA glc . The signaling pathways are governed by the chitin-responsive TCS sensor kinase ChiS and lead to the induction of chitin utilization and natural competence. We show that dephosphorylated EIIA glc inhibits both signaling pathways in a ChiS-dependent manner. This inhibition is different from classical catabolite repression that is caused by lowered levels of cyclic AMP. This work represents a newly identified connection between the PTS and chitin signaling pathways in V. cholerae and suggests a strategy whereby this bacterium can physiologically adapt to the existing nutrient status.KEYWORDS Vibrio cholerae, chitin, chitin utilization, natural competence, phosphoenolpyruvate:carbohydrate phosphotransferase system, two-component regulatory systems

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The Central Metabolism Regulator EIIA Glc Switches Salmonella from Growth Arrest to Acute Virulence through Activation of Virulence Factor Secretion

Cited by 26 publications

References 41 publications

A Genome-Wide Screen Reveals that the Vibrio cholerae Phosphoenolpyruvate Phosphotransferase System Modulates Virulence Gene Expression

A Genome-Wide Screen Reveals that the Vibrio cholerae Phosphoenolpyruvate Phosphotransferase System Modulates Virulence Gene Expression

Systematic genetic dissection of PTS in Vibrio cholerae uncovers a novel glucose transporter and a limited role for PTS during infection of a mammalian host

Glucose-Specific Enzyme IIA of the Phosphoenolpyruvate:Carbohydrate Phosphotransferase System Modulates Chitin Signaling Pathways in Vibrio cholerae

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