A Fur-like protein PerR regulates two oxidative stress response related operons dpr and metQIN in Streptococcus suis
© Zhang et al.; licensee BioMed Central Ltd. 2012
Received: 3 November 2011
Accepted: 2 May 2012
Published: 30 May 2012
Metal ions are important micronutrients in cellular metabolism, but excess ions that cause toxic reactive oxygen species are harmful to cells. In bacteria, Fur family proteins such as Fur, Zur and PerR manage the iron and zinc uptake and oxidative stress responses, respectively. The single Fur-like protein (annotated as PerR) in Streptococcus suis has been demonstrated to be involved in zinc and iron uptake in previous studies, but the reports on oxidative stress response and gene regulation are limited.
In the present study, the perR gene deletion mutant ΔperR was constructed in Streptococcus suis serotype 2 strain SC-19, and the mutant strain ΔperR exhibited less sensitivity to H2O2 stress compared to the wild-type. The dpr and metQIN were found to be upregulated in the ΔperR strain compared with SC-19. Electrophoretic mobility shift assays showed that the promoters of dpr and metQIN could be bound by the PerR protein. These results suggest that dpr and metQIN are members of the PerR regulon of S. suis. dpr encodes a Dps-like peroxide resistance protein, and the dpr knockout strains (Δdpr and ΔdprΔperR) were highly sensitive to H2O2. MetQIN is a methionine transporter, and the increased utilization of methionine in the ΔperR strain indirectly affected the peroxide resistance. Using a promoter–EGFP gene fusion reporting system, we found that the PerR regulon was induced by H2O2, and the induction was modulated by metal ions. Finally, we found that the pathogenicity of the perR mutant was attenuated and easily cleared by mice.
These data strongly suggest that the Fur-like protein PerR directly regulates dpr and metQIN and plays a crucial role in oxidative stress response in S. suis.
Iron and zinc are recognized as important micronutrients for bacteria, but excess of iron can catalyze the Fenton reactions, resulting in formation of toxic hydroxyl radicals . Similarly, an excess of zinc ions can also trigger the formation of hydroxyl radicals . Besides hydroxyl radicals, reactive oxygen species (ROS) such as superoxide radical and H2O2 are inevitably generated as byproducts of aerobic metabolism in bacteria . Additionally, during infection, ROS can be generated by the innate immune system. ROS can cause damage to many macromolecules including DNA, proteins and lipids [5, 6]. It is clear that oxidative stress and metal homeostasis are closely related. However, bacteria have evolved efficient mechanisms to maintain metal ion homeostasis and protect themselves from oxidative damage .
Fur family proteins are present widely in bacteria and play crucial roles in cellular processes. This family contains more than six different proteins. They are the sensors of iron (Fur and Irr) , zinc (Zur) , manganese  and nickel (Nur) , and the peroxide regulon repressor (PerR) . In the Gram-negative Escherichia coli, there are two Fur family proteins Fur and Zur. In contrast, there are three Fur-like proteins (Fur, Zur and PerR) in many Gram-positive bacteria such as Bacillus subtilis Clostridium acetobutylicum and Staphylococcus aureus. In B. subtilis, Fur regulates iron uptake and siderophore biosynthesis; Zur regulates two ABC zinc transporters; and PerR regulates the oxidative stress response [13, 14].
Streptococcus suis is economically a very important Gram-positive and facultative anaerobic bacterium that causes severe diseases in pigs and humans. As an emerging zoonotic pathogen, S. suis serotype 2 has become the predominant causative agent of adult human meningitis in Vietnam and Hong Kong . Two large outbreaks of human infections were reported in China in 1998 and 2005, resulting in 229 infections and 52 deaths [16, 17]. Like other bacterial pathogens, S. suis may also encounter both oxidative stress and metal starvation during infection. Thus, the regulation on the responses to oxidative stress and metal starvation by Fur-like proteins could be particularly important for S. suis survival in vivo and pathogenesis. However, only a single gene encoding a Fur-like protein has been found in each sequenced genome of S. suis, even in the genomes of most species of the genus Streptococcus. For example, the single Fur-like protein is encoded by SSU05_0310 in S. suis serotype 2 strain 05ZYH33 (GenBank accession no. CP000407). This protein has been defined as a zinc uptake regulator (Zur) , as well as an iron uptake regulator (Fur) in S. suis, but the research on its function in oxidative stress response is limited, whereas its homolog in Streptococcus pyogenes has been demonstrated to be a peroxide regulon repressor PerR [20–22]. In this study, the role of this Fur-like protein in peroxide resistance was confirmed in S. suis serotype 2. Therefore, we renamed this protein as PerR. At the same time, two target operons, dpr (dps-like peroxide resistance protein) and metNIQ (methionine ABC-type transporter), were identified and proved to play important roles in oxidative stress response.
Identification of a fur-like protein in S. Suis and other streptococci
Roles of PerR in H2O2 resistance in S. Suis
Our sequence analysis suggested that PerR might be involved in the oxidative stress response in S. suis, and therefore we constructed a perR knockout strain (ΔperR) and a functional complementing strain (CΔperR). The growth of the wild-type, mutant and complementary strains showed no obvious difference in TSB medium with 5% newborn bovine serum (data not shown).
Transcriptional regulation by PerR in S. Suis
The results of PerR regulon’s identification
Predicted target genesa
Function of genes
aromatic amino acid aminotransferase
cation transport ATPase
MATE efflux family protein
LacI family transcriptional regulator
peroxide resistance protein
phosphotyrosine protein phosphatase
ABC transporter ATP-binding protein
recombination factor protein
rRNA large subunit methyltransferase
trypsin-like serine protease
Roles of dpr in H2O2 resistance in S. Suis
H2O2 sensitivity analysis suggested that PerR was involved in oxidative stress response and we have found that dpr was directly regulated by PerR in S. suis. dpr encodes a peroxide resistance protein, previous study has found that dpr mutant was highly sensitive to H2O2. To test the role of dpr in H2O2 resistance, the dpr gene was inactivated in strains SC-19 and ΔperR. The resultant mutant strains Δdpr and ΔperRΔdpr were subjected to the H2O2 sensitivity assay. Both dpr mutant strains exhibited <1% survival after incubation with 10 mM H2O2 (Figure 2B). Inactivation of dpr led to near loss of H2O2 defensive capability in both Δdpr and ΔperRΔdpr strains. However, there was no obvious difference in the survival rate between Δdpr and ΔperRΔdpr, suggesting that the increased H2O2 resistance of the perR mutant probably results of the derepression of dpr.
Role of methionine in H2O2 resistance in S. Suis
To investigate the role of methionine in oxidative stress, the H2O2 sensitivity of strains in CDM with different concentrations of methionine was tested. As shown in Figure 5B, strain SC-19 showed the lowest survival rate in CDM lacking methionine, and the survival rates were increased when methionine was added. The same phenomenon was observed in strain ΔperR, except that ΔperR showed higher survival rates at every methionine concentration. These results indicated that the resistance to H2O2 in S. suis was related to methionine.
Role of PerR in pathogenicity in S. Suis
An experimental infection model in mice was designed to assess the role of PerR in pathogenicity. In the wild-type group, all of the mice presented severe clinical signs associated with septicemia and septic shock during the first day post-infection and then died from septicemia in this group. In contrast, the mice in the ΔperR group presented with partial clinical signs, three of eight infected mice survived during 1 dpi, and finally one mouse was alive at 7 dpi. Thus, as previously report , the mutant strain ΔperR was slightly attenuated in pathogenicity according to survival rate and clinical signs.
Survival of SC-19 and ΔperR in different organs in mice
Bacteria recovered from blood and tissues (×105 CFU)a
4.49 ± 3.24
2.37 ± 1.71
0.44 ± 0.04
4.10 ± 2.41
0.09 ± 0.05
4.22 ± 1.45
1.48 ± 0.11
1.03 ± 1.59
1.66 ± 1.11
0.07 ± 0.04
5.07 ± 3.07
1.42 ± 0.20
1.62 ± 1.33
3.84 ± 2.96
0.13 ± 0.12
0.01 ± 0.01
0.15 ± 0.09
0.35 ± 0.11
0.03 ± 0.02
0.22 ± 0.22
0.04 ± 0.04
As a pathogen, S. suis may encounter both oxidative stress and metal starvation during infection. Fur family proteins play important roles in metal ion homeostasis and oxidative stress responses in many bacteria. A single Fur-like protein was identified in S. suis, and in the rest of the genus Streptococcus, except for S. pneumoniae. The Fur-like protein in S. suis has been shown to regulate the zinc and iron uptake genes [18, 19]. In our study, the function of this Fur-like protein in oxidative stress response was characterized. We suggested that, in addition to its role in regulating zinc and iron uptakes, another important role of this Fur-like protein was to act as an oxidative stress response regulator in S. suis, and reannotated this Fur-like protein as PerR.
A recent research has found that the fur (perR) knock-out mutant in S. suis serotype 2 strain P1/7 was more sensitive to H2O2. However, in our study, an opposite result was observed, that deletion of perR in S. suis serotype 2 strain SC-19 resulted in increased resistance to H2O2. Deletion of PerR has been found to cause a high resistance ability to H2O2 in B. subtilis, C. acetobutylicumS. aureus, and in the single Fur containing S. pyogenes, and these results accord with our test in S. suis.
As a negative regulator, the high resistance to H2O2 in perR mutant may result from derepression of the PerR regulon. In many bacteria, one important member of PerR regulon for H2O2 resistance is catalase . However, all lactic acid bacteria including S. suis lack catalase, it is interesting to identify other potential PerR targets for H2O2 resistance in S. suis. qRT-PCR and EMSA tests showed that dpr and metQIN were directly regulated by PerR, and the expression of dpr and metQIN could be induced rapidly by physiological level of H2O2. These results suggested that one mechanism for oxidative stress response by PerR was derepression of PerR targets dpr and metQIN. Previous study found that feoAB was regulated by Fur (reannotated as PerR in our study) in S. suis P1/7 strain , however, in our study the PerR protein could not bind with feoAB promoter as well as we did not found a PerR-box in the promoter region (data not shown), suggesting that it is an indirectly regulation.
Dps family proteins have been identified in many bacteria including S. suis. In B. subtilis and S. pyogenes, the Dps homolog MrgA is derepressed when H2O2 oxidizes PerR [21, 29]. Usually, If the Fe2+ is present, H2O2 could be nonenzymatically cleaved into highly toxic hydroxyl radicals by Fenton reaction (H2O2 + Fe2+ → ·OH + ―OH + Fe3+). However, Dpr can prevent the Fenton-reaction by storing iron and converting Fe2+ to Fe3+-mineral (FeOOH) in a ferroxidase dependent way, resulting in avoiding formation of hydroxyl radicals. In addition, Dpr can bind DNA to protect DNA from oxidative damage in most bacteria but not in S. suis[30–32]. According with previous study, H2O2 resistance was markedly reduced in Δdpr. In our experiment, we found that the double mutant ΔperRΔdpr was also highly sensitive to H2O2 (Figure 2B). Although other PerR targets might be derepressed in ΔperR, H2O2 resistance ability was not obviously increased. It suggested that, in catalase negative S. suis, Dpr was especially crucial for H2O2 resistance, and the main reason for increased H2O2 resistance in ΔperR was derepression of dpr.
All amino acid residues of protein are susceptible to oxidative stress. However, methionine sulfoxide can be reduced to methionine by methionine sulfoxide reductase (Msr). During this reaction, Methionine helps the organisms to reduce H2O2 to H2O (Met + H2O2 → Met(O) + H2O; Met(O) + Th(SH)2 → Met + Th(S-S) + H2O) . In most species, such as humans, mice, yeast and bacteria, the cyclic oxidation and reduction of methionine residue plays an important role in defense against oxidative stress [33–36]. In our study, the metNIQ operon was found to be regulated by PerR. However, the metNIQ operon is repressed via the S-box system in B. subtilis and in some other bacteria . In contrast, we did not find the S-box in the promoter of metNIQ operon in S. suis, but it was replaced by a PerR-box (Figure 3C). A recent report also found that metNIQ operon was regulated by PerR in S. pyogenes via microarray assay . It seems, that metQIN is negatively regulated by Fur-like protein, is special in the streptococci. We found that metQIN operon could be induced by H2O2 in SC-19, and in metQIN derepressed ΔperR, methionine utilization was increased. Additionally, methionine concentration was found to be related to H2O2 resistance. These results suggested that, via controlling the methionine transport, methionine uptake could be regulated by PerR. Thus, oxidative stress response was indirectly affected.
PerR has been found to be necessary for full virulence of S. pyogenes. Our investigation found that the pathogenicity of perR mutant strain was attenuated. The decreased pathogenicity might be due to the reduced viability of mutant in the host. The fact that the viable number of mutant recovered from mice was much less than that of the wild-type, also supported this explanation. It seems that deletion of perR may lead to inappropriate expression of PerR-regulated genes and affect the normal growth. For example, knockout of perR led to iron starvation and the growth was inhibited in B. subtilis. It was reported that, because Dpr could store iron, the cytosolic iron would be efficiently scavenged when dpr was ectopic overexpressing in S. suis. It suggested that in ΔperR, the derepressed dpr would lead to cytosolic iron starvation and affect the growth.
These data strongly suggest that the Fur-like protein PerR regulates the oxidative stress response in S. suis. Two members of PerR regulon dpr and metQIN were identified in S. suis, dpr played a crucial role in H2O2 resistance and metQIN might indirectly affect the H2O2 resistance by controlling the methionine uptake. Mice infection model showed that the pathogenicity of perR mutant strain was attenuated.
Bacterial strains, plasmids, and growth conditions
Strains and plasmids used in this study
Strains or plasmids
Reference or source
Virulent Chinese S. suis serotype 2 isolate, wild-type
Gene perR inactive strain, Ermr
Complemented Δ perR strain, Ermr Spcr
Gene dpr inactive strain, Spcr
Gene perR and dpr inactive strain, Ermr Spcr
Pdpr-EGFP fusion inserted Wild-type, Spcr
Pdpr-EGFP fusion inserted Δ perR, Spcr
Cloning and expression host
In this lab
Thermosensitive allelic replacement vector
E. coli-S. suis shuttle vector
His tag fusion expression vector
A plasmid containing a EGFP gene
A mosaic plasmid designed to inactivate perR
A mosaic plasmid designed to inactivate dpr
Recombinant plasmid used for functional complementation of ΔperR
Recombinant plasmid used for inserting a Pdpr-EGFP fusion
Recombinant expression plasmid to produce His6-fused PerR protein
A plasmid containing an erm
Expression and purification of the PerR protein
Primers used in this study
General PCR amplification
Left arm of perR
Right arm of perR
perR and its promoter
Promoter of dpr
Promoter of 1772
Promoter of relA
Promoter of gidA
Construction of strains
To knockout the gene perR from S. suis SC-19, a thermosensitive homologous suicide vector pSET4s::perR carrying the left arm, right arm and the Erm resistance cassette (ermr) was constructed. The two arms were amplified from the chromosomal DNA of SC-19 by using primers 310 L01/310 L02 and 310R01/310R02 (Table 4), respectively. The ermr was amplified from the plasmid pAT18 by using primers ermF/ermR (Table 4). The recombinant plasmid pSET4s::perR was electrotransformed into SC-19, and the strains were selected on Spc and Erm plates as described previously . The suspected mutant strain ΔperR was verified by PCR, RT-PCR and Southern blot analysis. To construct a functional complementary strain for ΔperR, the complete coding sequencing of perR with its upstream promoter was amplified and cloned into the E. coli S. suis shuttle vector pSET2. The resultant plasmid pSET2::perR was electrotransformed into the mutant strain ΔperR. The resultant complementary strain was designated as CΔperR.
To monitor the regulation to dpr promoter, pSET4s:Pdpr-EGFP, a thermosensitive plasmid containing the transcriptional reporter system was constructed as follow: a 500-bp fragment containing the dpr promoter was amplified from SC-19 genomic DNA using primers PdprF/PdprR and cloned between the EcoRI and BamHI sites of the plasmid pSET4s, resulting in a plasmid pSET4s:Pdpr. The EGFP gene coding sequence was amplified from pMIDG301 (kindly donated by Dr Paul Langford, London, UK) using primers EGFP01/EGFP02 and cloned between the BamHI and PstI sites of the plasmid pSET4s:Pdpr. The resultant plasmid pSET4s:Pdpr-EGFP was electrotransformed into S. suis SC-19 and ΔperR, respectively. The fragment containing the dpr promoter was used as the homologous arm, through a single cross event, the thermosensitive plasmid pSET4s:Pdpr-EGFP was inserted into the genome at 28°C and the rest of plasmids in the strains were lost for continuous passage culture at 37°C. Spc was used in the whole process. The resultant strains were confirmed by PCR.
The CDM lacking zinc, iron and manganese was used as the basal medium. Overnight cultured S. suis strains SC-19:EGFP and ΔperR:EGFP were washed three times using the basal CDM, and then diluted 1:100 in the basal CDM supplemented with 50 μM Zn2+ and Fe2+ (or Mn2+) and 50 μg/ml Spc. Cells were cultured at 37°C for 3–4 h to early mid-log phase (OD600 = 0.3). The cells were induced by 10 μM H2O2 four times at every 15 min. One hour later, 1 ml of each sample was obtained and washed with PBS three times, green fluorescence was observed by fluorescence microscopy, and the mean fluorescence intensity (MFI) was assayed by flow cytometry. To remove the background of green fluorescence, strain SC-19 was used as the negative control.
H2O2 sensitivity assays
The disk diffusion assay to test H2O2 sensitivity was performed as described previously . The strain was cultured under near-anaerobic conditions to mid-log phase and 100-μl aliquots were spread on TSA plates. A sterile 5-mm-diameter filter disk containing 4 μl 1 M H2O2 was placed on the surface of the TSA plate. After incubation at 37°C for 12 h, the size of the area cleared of bacteria (inhibition zone) was measured.
For quantitative analysis, resistance of S. suis to H2O2 killing was tested as described previously , with slight modifications. Overnight cultured bacteria were diluted 100-fold into fresh TSB containing 5% newborn bovine serum in sealed tubes at 37°C without shaking (near-anaerobic conditions). When OD600 of the cells reached ~0.5, some cells were removed and incubation was continued at 37°C without agitation, and 10 mM H2O2 was added to the other part of the bacterial culture. Samples were collected at every 15 min for 1 hour after addition of H2O2. Appropriate bacterial dilutions were plated on TSA plates for viability counts. Survival rate was calculated by dividing the number of CFUs in the H2O2 challenge part with the number in the part without H2O2 challenge. For testing the effect of methionine on H2O2 resistance, overnight cultured bacteria were diluted 100-fold in CDM with different concentrations of methionine and then tested as above.
Amino acid analysis
Overnight cultured bacteria were washed three times with CDM and resuspended in the medium containing 100 mg/l methionine (OD600 = 0.1), and then incubated at 37°C for ~4 h. When the growth of cultures reached the late-log phase (OD600 = 1.6), medium samples were withdrawn from the bioreactor directly into a 2-ml tube. Samples were filtered through 0.22-μm filters. Amino acid concentrations of the filtered samples were determined using Amino Acid Analyzer L-8900 (Hitachi, Tokyo, Japan). All standards were commercial amino acids (Ajinomoto, Japan).
Electrophoretic mobility shift assay (EMSA)
Binding of recombinant PerR protein to DNA fragments containing the putative PerR-box was performed. The DNA fragments of the candidate promoters were amplified from S. suis SC-19 genomic DNA and purified by using the PCR Product Purification Kit (Sangon Biotech, Shanghai, China). Binding reactions were carried out in a 20-μl volume containing the binding buffer (20 mM Tris–HCl, pH 8.0; 50 mM KCl; 5% glycerol; 0.5 mM DTT; 25 μg/ml BSA, 100 ng poly dIdC), 0.1 μg promoter DNA and different amounts of purified recombinant PerR protein (0, 2, 4, and 8 μg). Binding reaction was incubated at room temperature for 15 min. The loading buffer was then added to the reaction mixtures and the electrophoresis was carried out with 5% native polyacrylamide DNA retardation gels at 100 V for ~1 h. Finally, the gels were stained with ethidium bromide. The 300-bp promoter of gidA was used as negative control.
Total RNAs of S. suis strains SC-19 and ΔperR were isolated as follows: overnight cultured bacteria in TSB medium with 5% newborn bovine serum was diluted 1:100 in fresh serum-containing TSB, and then incubated at 37°C to the mid-log phase (OD600 = 0.5). Total RNA was isolated and purified using the SV Total RNA Isolation System (Promega) according to the manufacturer’s instructions. The contaminating DNA was removed by DNase I treatment. Transcripts of the target genes were assessed by real-time RT-PCR using SYBR Green detection (TAKARA. Dalian. China) in an ABI 7500 system. gapdh gene served as the internal control. The primers using in the real-time RT-PCR are listed in Table 4. Differences in relative transcript abundance level were calculated using the 2–ΔΔCT method.
Mouse model of infection
All animal experiments were carried out according to the Regulation for Biomedical Research Involving Animals in China (1988). To detect the role of PerR in virulence in S. suis, a total of 24 female 6-week-old Balb/C mice were divided into three groups (8 mice per group). Animals in groups 1 and 2 were inoculated by intraperitoneal injection with 1 ml ~6.125 × 107 CFU of either S. suis SC-19 or ΔperR diluted in TSB. TSB medium was used as a negative control for group 3. Mice were observed for 1 week. To detect the role of FzpR PerR in colonization, two groups of female 6-week-old Balb/C mice were inoculated by intraperitoneal injection with 1 ml of 5 × 107 CFU of either SC-19 or ΔperR diluted in physiological saline. Blood, brain, lung and spleen were collected from mice (4 mice in each group) at 4, 7 and 11 days post infection (dpi). The samples were homogenized and subjected for bacterial viability count on TSA plates.
This work was supported by the National Basic Research Program of China (973 Program, 2012CB518802). We thank Dr. Yosuke Murakami for kindly providing the plasmids.
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