The Catabolite Control Protein E (CcpE) Affects Virulence Determinant Production and Pathogenesis of Staphylococcus aureus

Hartmann, Torsten; Baronian, Grégory; Nippe, Nadine; Voss, Meike; Schulthess, Bettina; Wolz, Christiane; Eisenbeis, Janina; Schmidt‐Hohagen, Kerstin; Gaupp, R.; Sunderkötter, Cord; Beißwenger, Christoph; Bals, Robert; Somerville, Greg A.; Herrmann, Mathias; Molle, Virginie; Bischoff, Markus

doi:10.1074/jbc.m114.584979

Cited by 35 publications

(34 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are several other regulators that were shown to impact cap expression, many of which act indirectly through intertwined regulatory circuits (summarised in http://onlinelibrary.wiley.com/doi/10.1111/mmi.13174/suppinfo). Previously, the impact of the transcriptional regulators SpoVG, sigma factor B, Arl and CcpE were analysed using immunofluorescence (Meier et al ., ; Schulthess et al ., ; Hartmann et al ., ). Mutations in these regulators led to a decrease in CP expression.…”

Section: Resultsmentioning

confidence: 97%

“…S3). Previously, the impact of the transcriptional regulators SpoVG, sigma factor B, Arl and CcpE were analysed using immunofluorescence (Meier et al, 2007;Schulthess et al, 2009a;Hartmann et al, 2014). Mutations in these regulators led to a decrease in CP expression.…”

Section: Impact Of Other Regulators and Growth Conditions For Cap Expmentioning

confidence: 99%

“…Usually Pcap activity correlates with CP synthesis, indicating that regulation occurs predominantly on the transcriptional level (Meier et al, 2007;Jansen et al, 2013;Hartmann et al, 2014;Romilly et al, 2014). Different environmental cues are signalled via the activity of several largely interactive regulatory systems composed of transcriptional factors CodY (Pohl et al, 2009;Majerczyk et al, 2010), CcpE (Ding et al, 2014;Hartmann et al, 2014), MgrA (Gupta et al, 2013;Romilly et al, 2014), SpoVG (Schulthess et al, 2009b) RpiR (Zhu et al, 2011), SbcDC (Chen et al, 2007) or two-component regulatory systems Kdp (Zhao et al, 2010), Air (Sun et al, 2012), Sae (Steinhuber et al, 2003;Luong et al, 2011) and Agr (Dassy et al, 1993;Pohlmann-Dietze et al, 2000;Luong et al, 2002). A central player in the network is the quorum sensing system Agr composed of the agrBDCA operon and the divergently transcribed RNAIII molecule (Novick and Geisinger, 2008;Thoendel et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phenotypic heterogeneity and temporal expression of the capsular polysaccharide in Staphylococcus aureus

George

Nguyen

Geiger

et al. 2015

Molecular Microbiology

Self Cite

View full text Add to dashboard Cite

SummaryBacteria respond to ever-changing environments through several adaptive strategies. This includes mechanisms leading to a high degree of phenotypic variability within a genetically homogeneous population. In Staphylococcus aureus, the capsular polysaccharide (CP) protects against phagocytosis, but also impedes adherence to endothelial cells and/or matrix proteins. We analysed the regulation of core biosynthesis genes (capA-P) necessary for CP synthesis using single-cell assays (immunofluorescence and promoter-activity). In persistent human carriers, we found a distinct subpopulation of nasal S. aureus to be CP positive. In vitro, cap expression is also heterogeneous and strongly growth-phase dependent. We asked whether this peculiar expression pattern (earlyOff/lateHeterogen) is orchestrated by the quorum system Agr. We show that the Agr-driven effector molecule RNAIII promotes cap expression largely via inactivation of the repressor Rot. High NaCl, deletion of CodY or Sae also resulted in higher cap expression but did not change the earlyOFF/ lateHeterogen expression pattern. Activity of the quorum system itself is largely homogenous and does not account for the observed heterogeneity of cap expression or the strictly growth phase dependent expression. Our findings are in contrast to the prevailing view that quorum sensing is the main driving force for virulence gene expression when bacterial cell densities increase.

show abstract

Section: Resultsmentioning

confidence: 97%

Section: Impact Of Other Regulators and Growth Conditions For Cap Expmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phenotypic heterogeneity and temporal expression of the capsular polysaccharide in Staphylococcus aureus

George

Nguyen

Geiger

et al. 2015

Molecular Microbiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several metabolite-responsive regulators have been identified in S. aureus (e.g., CcpA [47,48], CodY [49,50], CcpE [51,52], and Rex [53]) that link metabolism with virulence regulation. As examples, the carbon catabolite protein A (CcpA) responds to glucose-associated metabolic signals (54), whereas CodY responds to GTP and branched-chain amino acids (50,55).…”

mentioning

confidence: 99%

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus

et al. 2016

Self Cite

View full text Add to dashboard Cite

fIn Staphylococcus aureus, metabolism is intimately linked with virulence determinant biosynthesis, and several metabolite-responsive regulators have been reported to mediate this linkage. S. aureus possesses at least three members of the RpiR family of transcriptional regulators. Of the three RpiR homologs, RpiRc is a potential regulator of the pentose phosphate pathway, which also regulates RNAIII levels. RNAIII is the regulatory RNA of the agr quorum-sensing system that controls virulence determinant synthesis. The effect of RpiRc on RNAIII likely involves other regulators, as the regulators that bind the RNAIII promoter have been intensely studied. To determine which regulators might bridge the gap between RpiRc and RNAIII, sarA, sigB, mgrA, and acnA mutations were introduced into an rpiRc mutant background, and the effects on RNAIII were determined. Additionally, phenotypic and genotypic differences were examined in the single and double mutant strains, and the virulence of select strains was examined using two different murine infection models. The data suggest that RpiRc affects RNAIII transcription and the synthesis of virulence determinants in concert with B , SarA, and the bacterial metabolic status to negatively affect virulence. Staphylococcus aureus is a major human pathogen causing a diverse range of infections, from superficial skin and wound infections to life-threatening diseases such as bacteremia, endocarditis, osteomyelitis, deep tissue abscesses, or pneumonia (1). The pathogenicity of S. aureus is due in part to its ability to produce a large number of virulence determinants, including secreted proteins (e.g., toxins and proteases), cell wall-associated proteins (e.g., protein A and fibronectin binding proteins), and extracellular polysaccharides (i.e., capsule and polysaccharide intercellular adhesion). During colonization and infection of a host, S. aureus must adapt to rapidly changing environmental and nutritional conditions by coordinating the transcription and translation of physiologic and virulence genes (2). To coordinately control these cellular processes, S. aureus has evolved or acquired a network of regulators such as the recently identified family of proteins, RpiR, that affect pentose phosphate pathway activity and virulence determinant synthesis (3).Central to the regulatory network is the accessory gene regulator (Agr) system, a regulator of virulence determinant synthesis that responds to the bacterial population density (4). The agr locus consists of two divergent transcriptional units, RNAII and RNAIII, driven by the P2 and P3 promoters, respectively. RNAII comprises the agrBDCA operon, of which the agrBD gene products are involved in the synthesis, transport, and maturation of an autoinducing peptide (AIP). As the cell density increases, AIP accumulates in the extracellular milieu and when a threshold is achieved the two-component system AgrCA responds by activating transcription of both P2 and P3 promoters. The P3 promoter drives transcription of RNAIII, which is the re...

show abstract

“…In general, P cap activity correlates with CP synthesis, indicating that regulation occurs predominantly at the transcriptional level (Ouyang et al, 1999;Meier et al, 2007;Jansen et al, 2013;Hartmann et al, 2014;George et al, 2015). Yet, the data to explain the molecular mechanisms of cap regulation are puzzling.…”

Section: Introductionmentioning

confidence: 99%

Revisiting the regulation of the capsular polysaccharide biosynthesis gene cluster in Staphylococcus aureus

Keinhörster

Salzer

Duque‐Jaramillo

et al. 2019

Molecular Microbiology

Self Cite

View full text Add to dashboard Cite

Summary Capsular polysaccharide (CP) biosynthesis in Staphylococcus aureus is tightly controlled resulting in a heterogeneous phenotype within a population and CP being mainly detectable in nongrowing cells. Expression of the corresponding biosynthesis gene cluster is driven by one promoter element (Pcap). Here, we demonstrate that Pcap contains a main SigB‐dependent promoter. The SigB consensus motif overlaps with a previously described inverted repeat (IR) that is crucial for cap expression. The essentiality of the IR is derived from this region acting as a SigB binding site rather than as an operator site for the proposed cap activators RbsR and MsaB. Furthermore, Pcap contains an extensive upstream region harboring a weak SigA‐dependent promoter and binding sites for cap repressors such as SaeR, CodY and Rot. Heterogeneous CP synthesis is determined by SigB activity and repressor binding to the upstream region. SigB dependency and regulation by the upstream repressors are also sufficient to explain the temporal gene expression pattern at the transcriptional level. However, CP synthesis remains growth phase‐dependent even when transcription is rendered constitutive, suggesting additional posttranscriptional regulatory circuits. Thus, the interference of multiple repressors with SigB‐dependent promoter activity as well as post‐transcriptional mechanisms ensure the appropriate regulation of CP synthesis.

show abstract

The Catabolite Control Protein E (CcpE) Affects Virulence Determinant Production and Pathogenesis of Staphylococcus aureus

Cited by 35 publications

References 84 publications

Phenotypic heterogeneity and temporal expression of the capsular polysaccharide in Staphylococcus aureus

Phenotypic heterogeneity and temporal expression of the capsular polysaccharide in Staphylococcus aureus

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus

Revisiting the regulation of the capsular polysaccharide biosynthesis gene cluster in Staphylococcus aureus

Contact Info

Product

Resources

About