Opposite Effects of Mn2+and Zn2+on PsaR-Mediated Expression of the Virulence GenespcpA,prtA, andpsaBCAofStreptococcus pneumoniae

Kloosterman, Tomas G.; Witwicki, Robert M.; Kooi-Pol, Magdalena M. van der; Bijlsma, Jetta J. E.; Kuipers, Oscar P.

doi:10.1128/jb.00307-08

Cited by 65 publications

(118 citation statements)

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“…3, the E. faecalis zntA Ef and ef0759 mutants were significantly impaired in their capacity to survive inside macrophages when compared with their parent E. faecalis VE14089. The latter was even able to divide to some extent inside macrophages for the first 2 h and only later succumbed to macrophage defences, as reported previously (Kloosterman et al, 2008). Both proteins are, indeed, relevant for survival inside macrophages.…”

Section: Resultssupporting

confidence: 83%

“…Such a connection between zinc resistance and higher tolerance to oxidative stress and lysozyme has, to the best of our knowledge, never been described previously. A zinc burst, described to occur inside macrophages (Botella et al, 2011), could indirectly affect the mechanisms of oxidative stress response, as it is known that zinc is able to compete with manganese (Kloosterman et al, 2008;McDevitt et al, 2011), a crucial metal in oxidative stress response, in protein binding. McDevitt et al (2011) found that extracellular zinc inhibits manganese acquisition in Streptococcus pneumoniae by competing for binding to the solute-binding protein PsaA.…”

Section: Resultsmentioning

confidence: 99%

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Enterococcus faecalis zinc-responsive proteins mediate bacterial defence against zinc overload, lysozyme and oxidative stress

Abrantes

Lopes

2014

Microbiology

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Two Enterococcus faecalis genes encoding the P-type ATPase EF1400 and the putative SapB protein EF0759 were previously shown to be strongly upregulated in the presence of high concentrations of zinc. In the present work, we showed that a Zn2+-responsive DNA-binding motif (zim) is present in the promoter regions of these genes. Both proteins were further studied with respect to their involvement in zinc homeostasis and invasion of the host. EF0759 contributed to intramacrophage survival by an as-yet unknown mechanism(s). EF1400, here renamed ZntAEf, is an ATPase with specificity for zinc and plays a role in dealing with several host defences, i.e. zinc overload, oxidative stress and lysozyme; it provides E. faecalis cells with the ability to survive inside macrophages. As these three host defence mechanisms are important at several sites in the host, i.e. inside macrophages and in saliva, this work suggested that ZntAEf constitutes a crucial E. faecalis defence mechanism that is likely to contribute to the ability of this bacterium to endure life inside its host.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Enterococcus faecalis zinc-responsive proteins mediate bacterial defence against zinc overload, lysozyme and oxidative stress

Abrantes

Lopes

2014

Microbiology

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“…Since all S. pneumoniae strains tested so far have been unable to grow on fucose as a sole carbon and energy source, the role of this sugar in pneumococcal metabolism remains unclear (3). An alternative method based on the Zn 2ϩ -inducible promoter P czcD was described recently (7,17). To perform a gene depletion experiment with the Zn 2ϩ system, a DNA cassette containing a selectable antibiotic resistance marker and the gene of interest under the control of the P czcD promoter was inserted into the FIG.…”

Section: Discussionmentioning

confidence: 99%

“…Depletion of the selected gene takes place when the Zn 2ϩ concentration in the medium is reduced. As zinc plays an important role in pneumococcal physiology, the expression and function of a number of gene products are potentially affected by the levels of this metal ion (6,16,17,21). The Zn 2ϩ depletion system should therefore be used with caution.…”

Section: Discussionmentioning

confidence: 99%

Peptide-Regulated Gene Depletion System Developed for Use in Streptococcus pneumoniae

et al. 2011

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To facilitate the study of pneumococcal genes that are essential for viability or normal cell growth, we sought to develop a tightly regulated, titratable gene depletion system that interferes minimally with normal cellular functions. A possible candidate for such a system is the recently discovered signal transduction pathway regulating competence for natural transformation in Streptococcus thermophilus. This pathway, which is unrelated to the ComCDE pathway used for competence regulation in Streptococcus pneumoniae, has not been fully elucidated, but it is known to include a short unmodified signaling peptide, ComS*, an oligopeptide transport system, Ami, and a transcriptional activator, ComR. The transcriptional activator is thought to bind to an inverted repeat sequence termed the ECom box. We introduced the ComR protein and the ECom box into the genome of S. pneumoniae R6 and demonstrated that addition of synthetic ComS* peptide induced the transcription of a luciferase gene inserted downstream of the ECom box. To determine whether the ComRS system could be used for gene depletion studies, the licD1 gene was inserted behind the chromosomally located ECom box promoter by using the Janus cassette. Then, the native versions of licD1 and licD2 were deleted, and the resulting mutant was recovered in the presence of ComS*. Cultivation of the licD1 licD2 double mutant in the absence of ComS* gradually affected its ability to grow and propagate, demonstrating that the ComRS system functions as intended. In the present study, the ComRS system was developed for use in S. pneumoniae. In principle, however, it should work equally well in many other Gram-positive species.Gene disruption studies have shown that the genome of Streptococcus pneumoniae R6 contains at least 133 essential genes, 32 of which have no known function (23, 25). As these studies were carried out with laboratory-grown pneumococci, it is reasonable to assume that additional genes are essential for survival under natural conditions. For obvious reasons, functional studies of essential genes are experimentally demanding. The best approach is probably to express essential genes ectopically under the control of a tightly regulated, titratable promoter. This allows deletion of the native gene, while the level of transcription of the ectopically expressed gene can be manipulated to gain insight into its function. The same technique ought to be applied to studies of growth-defective genes whose absence affects bacterial growth and proliferation. In this way it should be possible to avoid the selection pressure exerted by deletion of growth-defective genes that gives rise to suppressor mutations which mask or distort the real phenotype of the mutant.Ideally, gene expression/depletion systems should not interfere with the normal physiology of the host bacterium. The ComRS signal transduction pathway, which regulates competence for natural transformation in Streptococcus thermophilus (9), has no close homologs in S. pneumoniae. We therefore considered it a pro...

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“…Zinc homeostasis is achieved by the tight control of storage systems and transporters with broad diversity (5,15,30,50). Bacterial responses to zinc have been studied by genome-wide transcriptional analyses in Escherichia coli (8,26), Bacillus subtilis (31), and Streptococcus pneumoniae (24), showing altered expression of numerous genes implicated in tolerance for and efflux of zinc and other metals, and also in general stress resistance. Conversely, zinc depletion in E. coli regulates a small number of genes involved in high-affinity zinc binding and uptake or encoding zinc-independent ribosomal proteins (18).…”

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confidence: 99%

Lactococcus lactis ZitR Is a Zinc-Responsive Repressor Active in the Presence of Low, Nontoxic Zinc Concentrations In Vivo

et al. 2011

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In the family Streptococcaceae, the genes encoding zinc ABC uptake systems (called zit or adc) are regulated by a coencoded MarR family member (i.e., ZitR or AdcR), whereas in the great majority of bacteria, these genes are regulated by Zur, the Fur-like zinc-responsive repressor. We studied the zit operon from Lactococcus lactis and its regulation in response to Zn(II) in vivo. zit transcription is repressed by Zn(II) in a wide concentration range starting from nontoxic micromolar levels and is derepressed at nanomolar concentrations. The level of zit promoter downregulation by environmental Zn(II) is correlated with the intracellular zinc content. The helix-turn-helix domain of ZitR is required for downregulation. In vitro, the purified protein is a dimer that complexes up to two zinc ligands per monomer and specifically binds two intact palindromic operator sites overlapping the ؊35 and ؊10 boxes of the zit promoter. DNA binding is abolished by the chelator EDTA or TPEN and fully restored by Zn(II) addition, indicating that the active repressor complexes Zn(II) with high affinity. These results suggest that derepression under starvation conditions could be an essential emergency mechanism for preserving Zn(II) homeostasis by uptake; under Zn(II)-replete conditions, the function of ZitR repression could be to help save energy rather than to avoid Zn(II) toxicity. The characterization of a MarR family zinc-responsive repressor in this report gives insight into the way Streptococcaceae efficiently adapt to Zn(II) fluctuations in their diverse ecological niches.

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Opposite Effects of Mn²⁺and Zn²⁺on PsaR-Mediated Expression of the Virulence GenespcpA,prtA, andpsaBCAofStreptococcus pneumoniae

Cited by 65 publications

References 90 publications

Enterococcus faecalis zinc-responsive proteins mediate bacterial defence against zinc overload, lysozyme and oxidative stress

Enterococcus faecalis zinc-responsive proteins mediate bacterial defence against zinc overload, lysozyme and oxidative stress

Peptide-Regulated Gene Depletion System Developed for Use in Streptococcus pneumoniae

Lactococcus lactis ZitR Is a Zinc-Responsive Repressor Active in the Presence of Low, Nontoxic Zinc Concentrations In Vivo

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