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. 2007 Oct;66(1):1-13.
doi: 10.1111/j.1365-2958.2007.05878.x.

Sucrose metabolism contributes to in vivo fitness of Streptococcus pneumoniae

Ramkumar Iyer  1 , Andrew Camilli
Affiliations

Sucrose metabolism contributes to in vivo fitness of Streptococcus pneumoniae

Ramkumar Iyer et al. Mol Microbiol. 2007 Oct.

Abstract

We characterized two sucrose-metabolizing systems -sus and scr- and describe their roles in the physiology and virulence of Streptococcus pneumoniae in murine models of carriage and pneumonia. The sus and scr systems are regulated by LacI family repressors SusR and ScrR respectively. SusR regulates an adjacent ABC transporter (susT1/susT2/susX) and sucrose-6-phosphate (S-6-P) hydrolase (susH). ScrR controls an adjacent PTS transporter (scrT), fructokinase (scrK) and second S-6-P hydrolase (scrH). sus and scr play niche-specific roles in virulence. The susH and sus locus mutants are attenuated in the lung, but dispensable in nasopharyngeal carriage VSports手机版. Conversely, the scrH and scr locus mutants, while dispensable in the lung, are attenuated for nasopharyngeal colonization. The scrH/susH double mutant is more attenuated than scrH in the nasopharynx, indicating SusH can substitute in this niche. Both systems are sucrose-inducible, with ScrH being the major in vitro hydrolase. The scrH/susH mutant does not grow on sucrose indicating that sus and scr are the only sucrose-metabolizing systems in S. pneumoniae. We propose a model describing hierarchical regulation of the scr and sus systems by the putative inducer, S-6-P. The transport and metabolism of sucrose or a related disaccharide thus contributes to S. pneumoniae colonization and disease. .

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Figures

Fig. 1
Fig. 1
The S-6-P hydrolase, susH, and the sus operon contribute to survival of S. pneumoniae in the murine lung. Loss of the S-6-P hydrolase, susH, or loss of the sus operon, sus, causes attenuation in the pneumonia model of infection in competition with wild-type cells. Loss of the second S-6-P hydrolase, scrH, causes only mild attenuation, with no additive attenuation in the double S-6-P hydrolase null, susH/scrH, or the double operon mutant, sus/scr, in competitions with wild type. Provision of a single copy of the susH gene in trans in the double S-6-P hydrolase null complements the in vivo defect.
Fig. 2
Fig. 2
The S-6-P hydrolase, scrH, contributes to colonization of the murine nasopharynx. Loss of the S-6-P hydrolase, scrH, causes attenuation in the nasopharyngeal colonization model of infection. In contrast, although the susH mutant is not attenuated, the double S-6-P hydrolase mutant susH/scrH is significantly more attenuated than scrH (P = 0.02) indicating that SusH might be active in the scrH mutant. Provision of scrH in trans completely rescues the colonization defect in the susH/scrH mutant.
Fig. 3
Fig. 3
The S-6-P hydrolase, scrH, is required for growth on sucrose in vitro. A. Alignment of the conserved sucrose-binding box sequences of SusH and ScrH along with those of some representative invertases from Gram-positive and Gram-negative bacteria, fungi and plants. The conserved β-fructosidase motif is underlined and the conserved aspartate residue is in bold. B. Phylogenetic tree describing the clustering of SusH and ScrH in relation to S-6-P hydrolases (invertases) from diverse bacterial, fungal and plant sources. SusH is more related to the fungal and plant enzymes while ScrH clusters with typical bacterial invertases. All the members share the sucrose-binding box motif. C. scrH has a pronounced growth defect on sucrose while susH is dispensable. Loss of both scrH and susH (susH/scrH) abrogates the ability of S. pneumoniae to utilize sucrose as the sole carbon source in vitro. Provision of scrH in trans restores growth of the susH/scrH mutant on sucrose. D. Wild-type and susH lysates of S. pneumoniae grown on sucrose show ‘sucrolytic’ activity with comparable kinetics of fructose accumulation over time. The scrH lysate shows severely decreased rate of sucrose hydrolysis. There is no detectable sucrose hydrolysis activity in the S-6-P hydrolase double mutant, susH/scrH.
Fig. 4
Fig. 4
Ribonuclease protection assays (RPAs) depicting regulation of the scr and sus operons by ScrR and SusR and sucrose. RNA was isolated from wild type, scrR, susR or scrH mutant S. pneumoniae strains after growth in rich medium (THY) or SDMM with sucrose as the sole carbon source (Sucrose). Transcripts were detected in 1–3 µg of total RNA by RPA. Band intensities were quantified and normalized to the intensity of the pneumolysin gene (ply) band. Radioactivity per lane per probe was arbitrarily fixed at 90 000 cpm. A. ScrR is a repressor of scrH, scrT and scrK (scrR) and growth on sucrose induces scrH, scrT and scrK (sucrose) in wild-type cells. Average intensity relative to the wild type from two independent experiments is reported above each lane. U indicates undigested ply (lane 1), scrH (lane 2), scrT (lane 3) and scrK (lane 4) probes. B. SusR is a repressor of susT1 and susX (susR) but growth on sucrose does not induce expression of susT1, susX or susH in wild-type cells. Growth on sucrose induces expression of susT1 and susX in the scrH mutant (scrH). Average intensity relative to the wild type from two independent experiments is reported above each lane, where applicable. Left: U indicates undigested susH (lane 1), susT1 (lane 2 – upper band) and susX (lane 2 – lower band) probes. Right: U indicates undigested susT1 (lane 1 – upper band), ply (lane 1 – middle band), susX (lane 1 – lower band) and susH (lane 2) probes.
Fig. 5
Fig. 5
A model describing the hierarchical induction of the sus and scr systems by the putative inducer sucrose-6-phosphate (S-6-P). A. susR and scrR genes code for the repressors, SusR and ScrR, which normally repress the expression of the downstream genes in the sus and scr operons respectively. S-6-P is formed inside the cell concomitant with entry via ScrT, the sucrose PTS transporter. Once inside, S-6-P derepresses the scr system leading to the expression of the S-6-P hydrolase, ScrH and the fructokinase, ScrK. ScrH activity is the predominant ‘sucrolytic’ activity in wild-type cells under these conditions. ScrH hydrolyses S-6-P to glucose-6-phosphate (G-6-P) and fructose. A small fraction of sucrose could enter the cell via the ABC transporter, SusT1/SusT2 and is converted to S-6-P via the action of an unknown kinase. B. In the scrH mutant, influx of S-6-P via ScrT causes derepression of the scr operon leading to expression of scrT and scrK. However, the lack of scrH leads to an increase in intracellular concentrations of S-6-P (wide, filled, upward-directed arrow). This condition triggers derepression of the sus operon causing the expression of the ABC system, susT1/susT2, the solute-binding component, susX, and the second S-6-P hydrolase, susH. The sus pathway hydrolase, SusH, hydrolyses S-6-P to G-6-P and fructose.
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