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Regulation of arginine acquisition and virulence gene expression in the human pathogen Streptococcus pneumoniae by transcription regulators ArgR1 and AhrC.

ABSTRACT: In this study, we investigated for the first time the transcriptional response of the human pathogen Streptococcus pneumoniae to fluctuating concentrations of arginine, an essential amino acid for this bacterium. By means of DNA microarray analyses, several operons and genes were found, the expression of which was affected by the concentration of arginine in the medium. Five of the identified operons were demonstrated to be directly repressed in the presence of high arginine concentrations via the concerted action of the ArgR-type regulators ArgR1 and AhrC. These ArgR1/AhrC targets encompass the putative amino acid transport genes artPQ, abpA, abpB, and aapA; the arginine biosynthetic genes argGH; and the virulence genes aliB and lmB/adcAII-phtD encoding an oligopeptide-binding lipoprotein and cell surface Zn(2+)-scavenging units, respectively. In addition, the data indicate that three of the amino acid transport genes encode an arginine ATP-binding cassette transporter unit required for efficient growth during arginine limitation. Instead of regulating arginine biosynthetic and catabolic genes as has been reported for other Gram-positive bacteria, our findings suggest that the physiological function of ArgR1/AhrC in S. pneumoniae is to ensure optimal uptake of arginine from the surrounding milieu.

SUBMITTER: Kloosterman TG

PROVIDER: S-EPMC3248006 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Regulation of arginine acquisition and virulence gene expression in the human pathogen Streptococcus pneumoniae by transcription regulators ArgR1 and AhrC.

Kloosterman Tomas G TG Kuipers Oscar P OP

The Journal of biological chemistry 20111114 52

In this study, we investigated for the first time the transcriptional response of the human pathogen Streptococcus pneumoniae to fluctuating concentrations of arginine, an essential amino acid for this bacterium. By means of DNA microarray analyses, several operons and genes were found, the expression of which was affected by the concentration of arginine in the medium. Five of the identified operons were demonstrated to be directly repressed in the presence of high arginine concentrations via t ...[more]

PMID: 22084243

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Project description:Streptococcus mutans is a primary cariogenic pathogen in humans. Arginine metabolism is required for bacterial growth. In S. mutans, however, the involvement of transcription factors in regulating arginine metabolism is unclear. The purpose of this study was to investigate the function and mechanism of ArgR family transcription factors in S. mutans. Here, we identified an ArgR (arginine repressor) family transcription factor named AhrC, which negatively regulates arginine biosynthesis and biofilm formation in S. mutans. The ahrC in-frame deletion strain exhibited slow growth and significantly increased intracellular arginine content. The strain overexpressing ahrC showed reduced intracellular arginine content, decreased biofilm biomass, reduced production of water-insoluble exopolysaccharides (EPS), and different biofilm structures. Furthermore, global gene expression profiles revealed differential expression levels of 233 genes in the ahrC-deficient strain, among which genes related to arginine biosynthesis (argJ, argB, argC, argD, argF, argG, argH) were significantly upregulated. In the ahrC overexpression strain, there are 89 differentially expressed genes, mostly related to arginine biosynthesis. The conserved DNA patterns bound by AhrC were identified by electrophoretic mobility shift assay (EMSA) and DNase I footprinting. In addition, the analysis of β-galactosidase activity showed that AhrC acted as a negative regulator. Taken together, our findings suggest that AhrC is an important transcription factor that regulates arginine biosynthesis gene expression and biofilm formation in S. mutans. These findings add new aspects to the complexity of regulating the expression of genes involved in arginine biosynthesis and biofilm formation in S. mutans. IMPORTANCE Arginine metabolism is essential for bacterial growth. The regulation of intracellular arginine metabolism in Streptococcus mutans, one of the major pathogens of dental caries, is unclear. In this study, we found that the transcription factor AhrC can directly and negatively regulate the expression of N-acetyl-gamma-glutamyl-phosphate reductase (argC), thus regulating arginine biosynthesis in S. mutans. In addition, the ahrC overexpression strain exhibited a significant decrease in biofilm and water-insoluble extracellular polysaccharides (EPS). This study adds new support to our understanding of the regulation of intracellular arginine metabolism in S. mutans.

Project description:UnlabelledStreptococcus pneumoniae is auxotrophic for arginine, and molecular analysis of the pneumococcal genome showed that the gene encoding an arginine-ornithine antiporter (ArcD) is organized in a cluster together with the arcABC genes encoding the arginine deiminase system (ADS) of pneumococci. The ADS consists of the arginine deiminase (AD), the catabolic ornithine carbamoyltransferase (cOCT), and the carbamate kinase (CK). Pneumococcal genomes contain three ArgR-type regulators (ArgR1, ArgR2, and AhrC) that are supposed to be involved in the regulation of arginine metabolism. Here, we identified ArgR2 of TIGR4 as the regulator of the ADS and ArcD. ArgR2 binds to promoter sequences of the arc operon, and the deficiency of ArgR2 in TIGR4 abrogates expression of the ADS, including the arginine-ornithine antiporter ArcD. Intranasal infection of mice and real-time bioimaging revealed that deletion of the arcABCDT genes attenuates TIGR4. However, the acute-pneumonia model and coinfection experiments indicated that the arginine-ornithine antiporter ArcD is essential to maintain fitness, while the deficiency of ADS enzymes has a minor impact on pneumococcal fitness under in vivo conditions. Strikingly, argR2 mutant TIGR4 outcompeted the wild type in the respiratory tract, suggesting an increase in fitness and further regulatory functions of ArgR2. In contrast to TIGR4, other pneumococci, such as D39, lacking expression of ArgR2, constitutively express the ADS with a truncated nonfunctional AD. On the basis of these results, we propose that the arginine-ornithine antiporter is essential to maintain pneumococcal fitness and that the genes of the ADS cluster are positively regulated in a strain-specific manner by ArgR2.ImportancePneumococci are the major etiologic agents of community-acquired pneumonia, causing more than 1.5 million deaths annually worldwide. These versatile pathogens are highly adapted to the nutrients provided by the host niches encountered. Physiological fitness is of major importance for colonization of the nasopharyngeal cavity and dissemination during invasive infections. This work identifies the regulator ArgR2 as the activator of the S. pneumoniae TIGR4 ADS and the arginine-ornithine transporter ArcD, which is needed for uptake of the essential amino acid arginine. Although ArgR2 activates ArcD expression and uptake of arginine is required to maintain pneumococcal fitness, the deficiency of ArgR2 increases TIGR4 virulence under in vivo conditions, suggesting that other factors regulated by ArgR2 counterbalance the reduced uptake of arginine by ArcD. Thus, this work illustrates that the physiological homeostasis of pneumococci is complex and that ArgR2 plays a key role in maintaining bacterial fitness.

Dataset Information

Regulation of arginine acquisition and virulence gene expression in the human pathogen Streptococcus pneumoniae by transcription regulators ArgR1 and AhrC.

Publications

Regulation of arginine acquisition and virulence gene expression in the human pathogen Streptococcus pneumoniae by transcription regulators ArgR1 and AhrC.

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