CRP-Mediated Carbon Catabolite Regulation of Yersinia pestis Biofilm Formation Is Enhanced by the Carbon Storage Regulator Protein, CsrA

Willias, Stephan P.; Chauhan, Sadhana; Lo, Chien-Chi; Chain, Patrick; Motin, Vladimir L.

doi:10.1371/journal.pone.0135481

Cited by 33 publications

(42 citation statements)

References 45 publications

(73 reference statements)

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“…In Yersinia spp., in addition to regulation of pla, Crp regulates expression of genes encoding the type III secretion system and its effectors (19), the anti-phagocytic capsule F1, and hundreds of other protein-coding genes and small noncoding RNAs (sRNAs) (20,21). In addition, Crp has been suggested to regulate biofilm formation in Y. pestis indirectly and with CsrA (22,23). In contrast to expression in Escherichia coli, expression of crp itself in Y. pestis is not directly auto-regulated (24,25) but is regulated by the PhoP response regulator (26).…”

mentioning

confidence: 99%

Depletion of Glucose Activates Catabolite Repression during Pneumonic Plague

Ritzert

Lathem

2018

J Bacteriol

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Bacterial pathogenesis depends on changes in metabolic and virulence gene expression in response to changes within a pathogen's environment. The plague-causing pathogen, , requires expression of the gene encoding the Pla protease for progression of pneumonic plague. The catabolite repressor protein Crp, a global transcriptional regulator, may serve as the activator of in response to changes within the lungs as disease progresses. By using gene reporter fusions, the spatial and temporal activation of the and promoters was measured in a mouse model of pneumonic plague. In the lungs, was highly expressed in bacteria found within large aggregates resembling biofilms, while expression increased over time independent of the aggregated state. Increased expression of and correlated with a reduction in lung glucose levels. Deletion of the glucose-specific phosphotransferase system EIIBC (PtsG) of rescued glucose levels in the lungs, resulting in reduced expression of both and We propose that activation of expression during pneumonic plague is driven by an increase of both Crp and cAMP levels following consumption of available glucose in the lungs by Thus, Crp operates as a sensor linking the nutritional environment of the host to regulation of virulence gene expression. Using as a model for pneumonia, we discovered that glucose is rapidly consumed, leading to a catabolite-repressive environment in the lungs. As a result, expression of the gene encoding the plasminogen activator protease, a target of the catabolite repressor protein required for pathogenesis, is activated. Interestingly, expression of the catabolite repressor protein itself was also increased in the absence of glucose but only in biofilms. The data presented here demonstrate how a bacterial pathogen senses changes within its environment to coordinate metabolism and virulence gene expression.

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mentioning

confidence: 99%

Depletion of Glucose Activates Catabolite Repression during Pneumonic Plague

Ritzert

Lathem

2018

J Bacteriol

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“…These data more likely suggest genes for regulating biofilm formation are controlled by environmental factors, such as temperature and growth in the flea (41,42). Carbon source is also known to play a role (13), and while we observed no difference in expression of the diguanylate cyclases in biofilms, they were significantly upregulated in glycerol compared to glucose (Dataset 1).…”

Section: Global Analysis Of Gene Expressionmentioning

confidence: 68%

“…While known for its role during catabolite repression and regulation of the lac operon, it is now appreciated that Crp regulates expression of other genes, including factors important during infection to connect changes in glucose availability to regulation of bacterial behaviors. Across γ-proteobacteria, Crp regulates biofilm formation (12,13), capsule production (14), the DNA damage response (15), toxin production (16,17), luminescence (18), and iron acquisition (19).…”

Section: Introductionmentioning

confidence: 99%

“…In turn, Crp regulates expression of the type III secretion system and the Pla protease essential for pneumonic plague (22)(23)(24). Crp also promotes biofilm formation via a mechanism involving the RNA-binding regulatory protein CsrA (13). Production of the main constituent of biofilms, poly-N-acetylglucosamine, is increased at 37°C in fully virulent strains of Y. pestis, suggesting additional roles for biofilm formation during mammalian infection (25).…”

Section: Introductionmentioning

confidence: 99%

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The Cyclic AMP Receptor Protein Regulates Quorum Sensing and Global Gene Expression in Yersinia pestis During Planktonic Growth and Growth in Biofilms

Ritzert

Minasov

Embry

et al. 2019

Preprint

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Cyclic adenosine monophosphate (cAMP) receptor protein (Crp) is an important transcriptional regulator of Yersinia pestis. Expression of crp increases during pneumonic plague as the pathogen depletes glucose and forms large biofilms within lungs. To better understand control of Y. pestis Crp, we determined a 1.8 Å crystal structure of the protein-cAMP complex. We found that compared to Escherichia coli Crp, C helix amino acid substitutions in Y. pestis Crp did not impact cAMP dependency of Crp to bind DNA promoters. To investigate Y. pestis Crp-regulated genes during plague pneumonia, we performed RNA-sequencing on both wild-type and ∆crp mutant bacteria growing in planktonic and biofilm states in minimal media with glucose or glycerol. Y.pestis Crp is found to dramatically alter expression of hundreds of genes dependent upon carbon source and growth state. Gel shift assays confirmed direct regulation of the malT and ptsG promoters and Crp was then linked to Y. pestis growth on maltose as a sole carbon source. Ironregulation genes ybtA and fyuA were found to be indirectly regulated by Crp. A new connection between carbon source and quorum sensing was revealed as Crp was found to regulate production of acyl-homoserine lactones (AHLs) through direct and indirect regulation of genes for AHL synthetases and receptors. AHLs were subsequently identified in the lungs of Y. pestis infected mice when crp expression is highest in Y. pestis biofilms. Thus, in addition to well-studied pla, other Crp-regulated genes likely have important functions during plague infection. IMPORTANCE Bacterial pathogens have evolved extensive signaling pathways to translate environmental signals into changes in gene expression. While Crp has long been appreciated for its role in regulating metabolism of carbon sources in many bacterial species, transcriptional profiling has revealed that this protein regulates many other aspects of bacterial physiology. The 3 plague pathogen, Y. pestis, requires this global regulator to survive in blood, skin, and lungs.During disease progression, this organism adapts to changes within these niches. In addition to regulating genes for metabolism of non-glucose sugars, we find the Crp regulates genes for virulence, metal acquisition and quorum sensing by direct or indirect mechanisms. Thus, this single transcriptional regulator, that responds to changes in available carbon sources, can regulate multiple critical behaviors for causing disease.

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“…A microarray analysis further demonstrated that multiple genes of the virulence plasmid associated Ysc type III secretion system are differentially expressed in a csrA mutant of Y. pseudotuberculosis [13]. Furthermore, the Csr system is implicated in the control of biofilm formation, resistance against antibiotic, osmotic, and heat stress, as well as numerous metabolic pathways [11,13,14]. A major feature is that CsrA adjusts the central carbon flow through the pyruvate-acetate node and the tricarboxylic acid cycle in response to nutrient availability [13].…”

Section: Trans-acting Rnas Of Yersiniamentioning

confidence: 99%