Differential regulation of Streptococcus mutans gtfBCD genes in response to copper ions

Chen, Pei-Min; Chen, Jen‐Yang; Chia, Jean-San

doi:10.1007/s00203-005-0076-2

Cited by 14 publications

(17 citation statements)

References 32 publications

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“…How do biofilms provide protection against copper-mediated killing of S. pyogenes? The copper-mediated repression of biofilm formation has been seen with other Gram-positive bacteria such as Staphylococcus aureus (74) and S. mutans (75). The addition of as little as 1 M copper is able to inhibit S. aureus biofilm formation (74).…”

Section: Figmentioning

confidence: 93%

“…Given that the S. pyogenes cop operon locus has homology to established cop operons of other species and that these operons play a role in tightly regulating intracellular copper levels, we assessed whether expression of this locus was responsive to copper. S. pyogenes cultures were incubated with a range of copper concentrations (5,10,15,25,75, and 100 M) for 45 min, followed by real-time quan- titative PCR to quantitate the levels of copY and copA mRNA expression. Gene expression was induced in a copper concentrationdependent manner, with copper concentrations as low as 10 M resulting in a statistically significant 2-fold increase of copY and copA gene expression levels (Fig.…”

Section: S Pyogenes Clinical Isolates Contain a Cop Operon-like Locusmentioning

confidence: 99%

“…The authors of that study suggested that the effect was due to copper repression of the positive biofilm regulators Agr and Sae (74). In S. mutans, copper exposure alters the expression of glucosyltransferase, a key enzyme necessary for the adhesion and formation of biofilms on the tooth surface (75). Although regulators such as Mga (76), Srv (32,(77)(78)(79)(80), CodY (81), and the CovRS two-component system (76) have been implicated in S. pyogenes biofilm formation, the direct and indirect effects of copper on their regulation have not yet been evaluated.…”

Section: Figmentioning

confidence: 99%

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Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ , in an M1T1 Clinical Strain of Streptococcus pyogenes

et al. 2015

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Infection with Streptococcus pyogenes is associated with a breadth of clinical manifestations ranging from mild pharyngitis to severe necrotizing fasciitis. Elevated levels of intracellular copper are highly toxic to this bacterium, and thus, the microbe must tightly regulate the level of this metal ion by one or more mechanisms, which have, to date, not been clearly defined. In this study, we have identified two virulence mechanisms by which S. pyogenes protects itself against copper toxicity. We defined a set of putative genes, copY (for a regulator), copA (for a P1-type ATPase), and copZ (for a copper chaperone), whose expression is regulated by copper. Our results indicate that these genes are highly conserved among a range of clinical S. pyogenes isolates. The copY, copA, and copZ genes are induced by copper and are transcribed as a single unit. Heterologous expression assays revealed that S. pyogenes CopA can confer copper tolerance in a copper-sensitive Escherichia coli mutant by preventing the accumulation of toxic levels of copper, a finding that is consistent with a role for CopA in copper export. Evaluation of the effect of copper stress on S. pyogenes in a planktonic or biofilm state revealed that biofilms may aid in protection during initial exposure to copper. However, copper stress appears to prevent the shift from the planktonic to the biofilm state. Therefore, our results indicate that S. pyogenes may use several virulence mechanisms, including altered gene expression and a transition to and from planktonic and biofilm states, to promote survival during copper stress. IMPORTANCEBacterial pathogens encounter multiple stressors at the host-pathogen interface. This study evaluates a virulence mechanism(s) utilized by S. pyogenes to combat copper at sites of infection. A better understanding of pathogen tolerance to stressors such as copper is necessary to determine how host-pathogen interactions impact bacterial survival during infections. These insights may lead to the identification of novel therapeutic targets that can be used to address antibiotic resistance.

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Section: Figmentioning

confidence: 93%

Section: S Pyogenes Clinical Isolates Contain a Cop Operon-like Locusmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ , in an M1T1 Clinical Strain of Streptococcus pyogenes

et al. 2015

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“…In S. mutans strain GS-5, copper irreversibly inhibited the activity of F-ATPases, thereby compromising the cell's ability to carry out glycolysis in acidic environments (27). Furthermore, this cation was shown to modulate the expression of the glucosyltransferase D gene (gtfD), whose products are associated with soluble glucan production and biofilm formation in S. mutans (28). Like the genomes of many Gram-positive bacteria, the genome sequence of S. mutans does not appear to encode proteins or enzymes that require copper for their functional activity (29).…”

mentioning

confidence: 99%

The copYAZ Operon Functions in Copper Efflux, Biofilm Formation, Genetic Transformation, and Stress Tolerance in Streptococcus mutans

et al. 2015

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In bacteria, copper homeostasis is closely monitored to ensure proper cellular functions while avoiding cell damage. Most Gram-positive bacteria utilize the copYABZ operon for copper homeostasis, where copA and copB encode copper-transporting P-type ATPases, whereas copY and copZ regulate the expression of the cop operon. Streptococcus mutans is a biofilm-forming oral pathogen that harbors a putative copper-transporting copYAZ operon. Here, we characterized the role of copYAZ operon in the physiology of S. mutans and delineated the mechanisms of copper-induced toxicity in this bacterium. We observed that copper induced toxicity in S. mutans cells by generating oxidative stress and disrupting their membrane potential. Deletion of the copYAZ operon in S. mutans strain UA159 resulted in reduced cell viability under copper, acid, and oxidative stress relative to the viability of the wild type under these conditions. Furthermore, the ability of S. mutans to form biofilms and develop genetic competence was impaired under copper stress. Briefly, copper stress significantly reduced cell adherence and total biofilm biomass, concomitantly repressing the transcription of the gtfB, gtfC, gtfD, gbpB, and gbpC genes, whose products have roles in maintaining the structural and/or functional integrity of the S. mutans biofilm. Furthermore, supplementation with copper or loss of copYAZ resulted in significant reductions in transformability and in the transcription of competence-associated genes. Copper transport assays revealed that the ⌬copYAZ strain accrued significantly large amounts of intracellular copper compared with the amount of copper accumulation in the wild-type strain, thereby demonstrating a role for CopYAZ in the copper efflux of S. mutans. The complementation of the CopYAZ system restored copper expulsion, membrane potential, and stress tolerance in the copYAZ-null mutant. Taking these results collectively, we have established the function of the S. mutans CopYAZ system in copper export and have further expanded knowledge on the importance of copper homeostasis and the CopYAZ system in modulating streptococcal physiology, including stress tolerance, membrane potential, genetic competence, and biofilm formation. IMPORTANCE S. mutans is best known for its role in the initiation and progression of human dental caries, one of the most common chronic diseases worldwide. S. mutans is also implicated in bacterial endocarditis, a life-threatening inflammation of the heart valve. The core virulence factors of S. mutans include its ability to produce and sustain acidic conditions and to form a polysaccharide-encased biofilm that provides protection against environmental insults. Here, we demonstrate that the addition of copper and/or deletion of copYAZ (the copper homeostasis system) have serious implications in modulating biofilm formation, stress tolerance, and genetic transformation in S. mutans. Manipulating the pathways affected by copper and the copYAZ system may help to develop potential therapeutics to prev...

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“…9 Moreover, Streptococcus mutans produces a glucan-rich extracellular polymeric matrix that retains metal ions to considerably higher concentrations within the plaque than in the surrounding environment. 10 In drinking water, the ability of metal ions to interfere with the growth of S mutans has previously been investigated. 11 However, little is known about changes in the physiology of this species induced by ions from orthodontic appliances.…”

Section: +mentioning

confidence: 99%

Virulence modulation of Streptococcus mutans biofilms by metal ions released from orthodontic appliances

Rymovicz

Ronsani

Grégio

et al. 2013

The Angle Orthodontist

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Differential regulation of Streptococcus mutans gtfBCD genes in response to copper ions

Cited by 14 publications

References 32 publications

Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ , in an M1T1 Clinical Strain of Streptococcus pyogenes

Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ , in an M1T1 Clinical Strain of Streptococcus pyogenes

The copYAZ Operon Functions in Copper Efflux, Biofilm Formation, Genetic Transformation, and Stress Tolerance in Streptococcus mutans

Virulence modulation of Streptococcus mutans biofilms by metal ions released from orthodontic appliances

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