AI-2-dependent gene regulation in Staphylococcus epidermidis
© Li et al; licensee BioMed Central Ltd. 2008
Received: 25 October 2007
Accepted: 08 January 2008
Published: 08 January 2008
Autoinducer 2 (AI-2), a widespread by-product of the LuxS-catalyzed S-ribosylhomocysteine cleavage reaction in the activated methyl cycle, has been suggested to serve as an intra- and interspecies signaling molecule, but in many bacteria AI-2 control of gene expression is not completely understood. Particularly, we have a lack of knowledge about AI-2 signaling in the important human pathogens Staphylococcus aureus and S. epidermidis.
To determine the role of LuxS and AI-2 in S. epidermidis, we analyzed genome-wide changes in gene expression in an S. epidermidis luxS mutant and after addition of AI-2 synthesized by over-expressed S. epidermidis Pfs and LuxS enzymes. Genes under AI-2 control included mostly genes involved in sugar, nucleotide, amino acid, and nitrogen metabolism, but also virulence-associated genes coding for lipase and bacterial apoptosis proteins. In addition, we demonstrate by liquid chromatography/mass-spectrometry of culture filtrates that the pro-inflammatory phenol-soluble modulin (PSM) peptides, key virulence factors of S. epidermidis, are under luxS/AI-2 control.
Our results provide a detailed molecular basis for the role of LuxS in S. epidermidis virulence and suggest a signaling function for AI-2 in this bacterium.
Quorum sensing is the cell population density-dependent regulation of gene expression by small signaling molecules, called autoinducers (AI) . Many bacteria have several quorum sensing systems. For example, in the extensively studied Vibrio harveyi, there are two classes of quorum-sensing systems, one of which utilizes an acylhomoserine lactone as signal (AI-1), and the other a signal molecule commonly referred to as AI-2 . The biochemical synthesis of AI-2 involves several enzymatic steps starting from S-adenosylmethionine (SAM), particularly that catalyzed by LuxS, which produces AI-2 as a side product in addition to the primary role of this enzyme in the activated methyl cycle metabolism .
Most quorum-sensing autoinducers are specific for a narrow range of organisms and promote intra-species communication. In contrast, the widely conserved AI-2 has been proposed to allow for communication between species . In fact, more than 55 bacterial species are known to possess a gene homologous to luxS, and many produce AI-2 like activities . Since the discovery of AI-2 in V. harveyi, many organisms have been shown to regulate genes specifying diverse functions in a luxS-dependent manner, such as virulence factors in Streptococcus pneumoniae , E. coli (EHEC) O157:H7 , and Streptococcus pyogenes ; motility in Campylobacter jejuni , and biofilm formation in Streptococcus gordonii , E. coli K-12 , Bacillus cereus , Streptococcus mutans , and Klebsiella pneumonia . However, the function of AI-2 in most bacteria is not completely understood, owing to the fact that distinguishing between a genuine signal and a mere role as a metabolic side product is difficult . Clear evidence for a signal function can be derived from the discovery of AI-2-specific sensor/regulator systems and transporters. In V. harveyi, AI-2 is detected by a two-component system called LuxP/LuxQ [16, 17], whose AI-2 dependent activation results in the modulation of gene transcription. However, LuxP homologues are found only in Vibrio . In non-Vibrio species, the only genes shown to be directly regulated by AI-2 encode an ABC transporter in Salmonella enterica serovar Typhimurium named Lsr, which in that species is responsible for AI-2 uptake [19, 20].
Staphylococcus epidermidis is the most frequent cause of nosocomial sepsis and catheter-related infection . S. epidermidis has one well-characterized quorum-sensing system termed agr for accessory gene regulator [22, 23]. Additionally, like many other bacteria, S. epidermidis contains a luxS gene and produces AI-2 . In S. aureus, inactivation of luxS strains does not affect virulence-associated traits, such as the production of hemolysins and extracellular proteases, biofilm formation, and the agr system . In contrast, S. epidermidis luxS has been shown to influence biofilm formation in vitro and enhance virulence in a rat model of biofilm-associated infection . However, whether AI-2 functions as a signaling molecule in staphylococci has remained a matter of debate, mostly because evidence was only derived from the comparison of luxS mutants with the corresponding wild-type strains, and sensors or transporters for AI-2 in Staphylococcus species are not known. Therefore, to gain further insight into the role of AI-2 in staphylococci, and specifically in S. epidermidis, we synthesized AI-2 using S. epidermidis Pfs and LuxS enzymes and analyzed AI-2-dependent gene regulation using transcriptional profiling in wild-type, luxS mutant, and luxS mutant strain with exogenous addition of AI-2. AI-2 regulated genes included genes involved in glycol-, nucleotide, amino acid, and nitrogen metabolism, but also virulence-associated genes coding for the pro-inflammatory PSM peptides, lipase, and the bacterial apoptosis Lrg proteins. Our study suggests that AI-2 has a signaling function in S. epidermidis and an important role in the control of metabolism and virulence.
Characterization of the S. epidermidis luxS mutant
In vitro production of AI-2 by purified Pfs and LuxS and luxS-independent removal of AI-2 from cultures
In vitro AI-2 production from SAH using purified proteins
Normalized fold induction
AI-2 can be removed from culture supernatants in a luxS-independent manner, as shown in Pseudomonas fluorescens , which does not have luxS. Similarly, we found that the S. epidermidis luxS mutant strain had the capacity to remove AI-2 activity from culture supernatants, while AI-2 in controls was stable over the same period of time (Fig. 1C). It is not clear at this point whether the removal of AI-2 is due to it being metabolized or imported for signaling purposes.
AI-2 dependent gene regulation in S. epidermidis
Gene regulatory responses in S. epidermidis wild-type, ΔluxS and ΔluxS with exogenous AI-2
Hexose phosphate transport protein
PTS system, lactose-specific IIA component
Tagatose 1,6-diphosphate aldolase
PTS system, IIBC components
Gluconate transporter, permease protein
Gluconate operon transcriptional repressor
Ribose transport protein
PTS system, fructose-specific IIABC components
Phosphoribosylformylglycinamidine synthase, PurS protein
Phosphoribosylformylglycinamidine synthase I
Phosphoribosylformylglycinamidine synthase II
Phosphoribosylaminoimidazolecarboxamide formyltransferase/IMP cyclohydrolase
Phosphoribosylamine – glycine ligase
Amino acid metabolism
Delta-1-pyrroline-5-carboxylate dehydrogenase, putative
Acetoin dehydrogenase, E3 component, dihydrolipoamide dehydrogenase
Acetoin dehydrogenase, E1 component, alpha subunit
Acetoin dehydrogenase, E1 component, beta subunit
Nitrite extrusion protein
Respiratory nitrate reductase, gamma subunit
Respiratory nitrate reductase, delta subunit
Respiratory nitrate reductase, beta subunit
Portal protein, truncation
Antiholin-like protein LrgB
Major facilitator superfamily protein
Transcriptional regulator CadC
In recent years, the skin commensal microorganism S. epidermidis, has emerged as a leading cause of hospital-acquired infections . S. epidermidis infections are primarily associated with the use of medical devices such as venous catheters. Many regulatory systems control virulence-associated traits in S. epidermidis . Specifically, we have recently reported that a luxS mutant strain of S. epidermidis showed increased biofilm formation in vitro and enhanced virulence in a rat model of biofilm-associated infection . On the contrary, inactivation of luxS in various S. aureus strains has been reported not to affect virulence-associated traits . In further contrast to S. aureus, we show here that AI-2 activity in S. epidermidis was not maintained in stationary growth phase, but quickly decreased after obtaining a maximum during exponential growth. Thus, the role of AI-2 in staphylococci remains a matter of debate and there might be species-specific differences.
To gain further insight into luxS-dependent gene regulation and AI-2-dependent signaling in S. epidermidis, we used genome-wide transcriptional profiling. We synthesized AI-2 with over-expressed S. epidermidis enzymes and used the synthesized AI-2 in transcriptional profiling experiments to validate the signal role of AI-2. As main results of our studies, we detected that (i) externally added AI-2 almost completely restored gene expression patterns of the wild-type strain in the luxS mutant strain and (ii) S. epidermidis regulates virulence-associated factors in addition to metabolism in an AI-2-dependent fashion. Importantly, there was dramatic AI-2-dependent alteration of PSM expression. PSMs have been recently recognized as key pro-inflammatory and immune evasion factors in S. epidermidis and S. aureus [27, 28, 31] and very likely have an additional function in biofilm development . Further, we did not observe any influence of luxS on agr, a quorum-sensing system with a pronounced regulatory effect on PSM expression [28, 31] and therefore, luxS-dependent regulation of PSMs occurs via a yet undiscovered pathway. Moreover, we observed AI-2-dependent regulation of the antiholin protein LrgB, a possible main player in induced cell death in bacteria and DNA-dependent bacterial biofilm formation [32, 33]. Interestingly, we did not find the ica genes coding for production of the biofilm exopolysaccharide PIA among the genes regulated by AI-2 under the conditions used (during exponential growth at high activity of AI-2), which contrasts our previous findings that demonstrated luxS-dependent control of ica during later growth stages , when AI-2 activity is low. These findings may suggest that expression of the ica genes is impacted by the metabolic function of LuxS rather than AI-2 control, a hypothesis that remains to be validated.
Our results indicate important species-specific differences in luxS-dependent gene regulation between S. epidermidis and S. aureus. Further, based on the complementation with synthesized AI-2 and the inclusion of virulence genes in the luxS regulon, our study suggests that AI-2 has a signaling function in S. epidermidis. However, AI-2 signaling in staphylococci needs to be confirmed on a molecular level showing how AI-2 interacts with an external sensor, or alternatively, is imported into the cell for an internal sensor mechanism.
Bacterial strains and growth conditions
Bacterial strains and plasmids used in this study
Relevant genotype and property
luxS mutant (luxS- ermr)
recA1 endA1 gyrA96 thi-1 hsdR17 supE44 relA1 lac [F' proAB lacIqZΔM15 Tn10 (Tetr)]
K12 derivative, Nals Strs Rifs Thi- Lac- Ara- Gal+ Mtl- F- RecA+ Uvr+ Lon+ [pREP4 KanR]
F-,omp T, hsd S(rB-, mB-), gal
luxN::Tn5(sensor-1- sensor-2+), AI-2 reporter strain
lac Iq, 3.4 kb, Apr, T5, C-terminal 6 × His-tag
pQE-9 containing the luxS gene of S. epidermidis 1457
lac Iq, 4.9 bp, Apr, GST gene fusion vector
pGEX-4T-1 containing the pfs gene of S. epidermidis 1457
Overexpression and purification of LuxS and Pfs
The pfs gene was cloned and overexpressed as a glutathione-S-transferase (GST) fusion. The luxS gene was cloned and overexpressed as histidine residue-tagged (6 × His tag) fusion. Primers for amplification of pfs and luxS genes from S. epidermidis 1457 genomic DNA were as follows. For amplification of the pfs gene, the primers used were 5'-GCTTTATAAATGAGGTGTGAAAGGATCC ATGATAG-3' and 5'-CAATATCTTTTCACCTGAATTC TTATAATGATTCT-3'. For amplification of the luxS gene, the primers used were 5'-CAATAAGGAGGATGTCGAC ATGACTAAAATGAATG-3' and 5'-TTAGTTGTATTGTCTGCAG TTTACCTTCTCCGTAG-3'. PCR products were purified, digested using Bam HI and Eco RI for pfs and SaI I and Pst I for luxS. The pfs gene was cloned into the GST gene fusion vector pGEX-4T-1 (Amersham Biosciences), and the recombinant vector pGEX-pfs was maintained in E. coli strain BL21 (Amersham Biosciences) for overexpression. The luxS gene was cloned into the His-tag fusion vector pQE-9 (Qiagen), the recombinant vector pQE-luxS was transferred to E. coli strain XL1 blue (Qiagen) for propagating plasmids and then transferred to E. coli strain SG13009 [pREP4] (Qiagen) for overexpression. Unless otherwise noted, cultures of these two strains were grown at 37°C with aeration to an OD600 of 1.0. IPTG was added to a final concentration of 0.5 mM, the cultures were incubated with aeration for an additional 5 h, and cells were harvested. For recombinant Pfs, the fusion protein was purified using the GST-Tag purification Kit (Chemicon) according to the manufacturer's instructions. For recombinant LuxS, the fusion protein was purified on Ni-NTA agarose matrix columns by washing with 10 volumes of 50 mM NaH2PO4, 300 mM NaCl, 20 mM imidazole, pH 8.0, followed by elution with 5 volumes of 50 mM NaH2PO4, 300 mM NaCl, 100 mM imidazole, pH 8.0. The purified fusion proteins were concentrated in Centriprep-10 concentrators (Amicon) and dialysed against 10 mM sodium phosphate buffer (pH 7.5) using PD-10 Desalting columns (Amersham Biosciences). The sizes of the Pfs GST fusion protein and the LuxS His-tag fusion protein were confirmed by SDS-PAGE.
In vitro production of AI-2
Commercially available S-adenosylhomocysteine (SAH, Sigma) was used as the substrate for AI-2 synthesis . In vitro AI-2 synthesis reactions were carried out at 37°C. SAH (1 mM) was incubated with 1 mg/ml purified Pfs in 10 mM sodium phosphate buffer (pH 7.5) for 1 h, and the reactions were filtered through Ultrafree-10 units (Amicon). Subsequently, 1 mg/ml purified LuxS in 10 mM sodium phosphate buffer (pH 7.5) was added, and the reaction mixture was incubated for another hour. After incubation, reactions were filtered through the same filters as described above to remove protein from the reaction product.
The AI-2 bioassay that uses the V. harveyi reporter strain BB170 was performed as described . Briefly, the V. harveyi reporter strain was grown overnight at 30°C with aeration in AB medium, diluted 1:5000 into fresh AB medium, and 90 μl of the diluted cells were added to microtiter wells containing 10 μl of the samples to be tested for AI-2 activity. Sodium phosphate buffer (10 mM, pH 7.5) or medium alone was added as negative control. The microtiter dishes were shaken in a rotary shaker at 180 rpm at 30°C. Every hour, light production was measured using a Microlumatplus LB 96 V luminometer (Berthold). All assays were repeated at least three times.
S. epidermidis microarray experiments
Total RNA was isolated using an RNeasy Mini Kit (Qiagen) as recommended in a standard protocol. In brief, cell pellets were washed with RNase-free water, resuspended in 700 μl of RLT Buffer supplemented with β-mercaptoethanol (10 μl β-mercaptoethanol per 1 ml RLT). The bacterial suspension was transferred to a 2-ml FastPrep lysing tube (Q-BioGene). The cells were lysed in a Bio101 high-speed homogenizer (Savant Instruments), at the following setting: speed, 6.0; time, 20 s. The lysate was incubated on ice for 5 min and centrifuged at 15,000 rpm at 4°C for 15 min. The supernatant was collected and diluted with 500 μl of 100% ethanol. Samples were mixed and transferred to an RNeasy mini column. RNA isolation was performed according to the manufacturer's instructions. Remaining DNA was removed using RNase-free DNase I (Amersham Biosciences). Removal of contaminant DNA was confirmed by PCR. The reaction product was cleaned up with an RNeasy mini column. cDNA was synthesized and labeled according to the manufacturer's suggestions for Affymetrix antisense genome arrays (Affymetrix) as described . A gel shift assay with NeutrAvidin (Pierce Biotechnology) was performed to estimate the labeling efficiency based on the instructions from Affymetrix. Biotinylated S. epidermidis cDNA was hybridized to custom Affymetrix GeneChips (RMLChip 3) with 98.9% coverage of genes from S. epidermidis RP62A (2467 probe sets of 2494 ORFs) and scanned according to standard GeneChip protocols (Affymetrix). Each experiment was replicated at least 3 times. Affymetrix GeneChip Operating Software GCOS v1.4 was used to perform the preliminary analysis of the custom chips at the probe-set level. Subsequent data analysis was performed as described . To be included in the final gene list, gene expression must have been changed at least 2-fold for one of the treatments. The complete set of microarray data was deposited in NCBIs Gene Expression Omnibus  and is accessible through GEO Series accession number GSE9427.
Quantitative reverse-transcription (RT) polymerase chain reaction (PCR)
Oligonucleotide primers and probes used for RT-PCR
Antiholin-like protein LrgB
Nitrite extrusion protein
PTS system, fructose-specific IIABC components
Detection and quantitation of PSMs in bacterial culture filtrates
High-pressure liquid chromatography – mass spectrometry (HPLC-MS) was used to detect and quantify PSMs in bacterial culture supernatants. One hundred-microliter samples from cultures were injected onto an analytical reversed-phase column (Zorbax C8, 2.1 × 30 mm; Agilent). A gradient from 0.1% trifluoroacetic acid (TFA) in 50% acetonitrile/50% water to 0.1% TFA in 90% acetonitrile/10% water was applied by use of an Agilent 1100 system connected to a VL trap mass spectrometer.
This work was supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases, NIH.
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