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1 Department of Bacteriology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho Mizuho-ku, Nagoya 467-8601, Japan
2 Department of Molecular Bacteriology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya 466-8550, Japan
3 Department of Microbiology, Aichi Prefectural Institute of Public Health, Nagare 7-6, Tsuji-machi, Kita-ku, Nagoya 462-8576, Japan
Correspondence
Tadao Hasegawa
tadaoh{at}med.nagoya-cu.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Hoge et al., 1993; Schwartz et al., 1990; Stevens, 1994; Stevens et al., 1989; Hasegawa et al., 2004). Recently, case reports referring to STSS caused by the Lancefield group C streptococci (GCS) and G streptococci (GGS) have also accumulated (Assimacopoulos et al., 1997; Barnham et al., 2002; Eskens et al., 1995; Hirose et al., 1997; Keiser & Campbell, 1992; Kugi et al., 1998; Natoli et al., 1996; Ojukwu et al., 2001; Roth et al., 1999; Wagner et al., 1996).
The NAD-glycohydrolase (NADase; Nga) of GAS is a secreted protein that has been implicated in the pathogenesis of diseases including STSS and necrotizing fasciitis (Cunningham, 2000; Bricker et al., 2005; Meehl et al., 2005). β-NAD+ is universally important in numerous essential redox and energy-producing biological reactions. Therefore the ability of NADase to cleave β-NAD, depleting intracellular NAD pools, is thought to be one of the components of GAS toxicity (Meehl et al., 2005; Stevens et al., 2000; Michos et al., 2006). NADase is also toxic to bacterial cells themselves; therefore GAS genomes carry the ifs gene, whose product is an endogenous inhibitor of NADase.
Severely invasive GAS infections emerged in the late 1980s. Stevens et al. (2000) reported that all M-1 GAS strains isolated in the United States between 1988 and 1997 were NADase-positive while virtually all strains isolated prior to 1988 were NADase-negative. Regarding the shift in M-1 GAS from NADase-negative to NADase-positive, Stevens et al. (2000) rejected the possible explanation that recent M-1 isolates had acquired the gene via a mobile element, since all GAS isolates examined, even those that were NADase-negative, possessed the NADase gene (nga). The deduced Nga amino acid sequence from both NADase-positive (88-003, 96-004, 99-025 and 99-024) and NADase-negative GAS isolates (SF370, 75062 and CS190) indicated extensive homology. There are six conserved amino acids shared by the NADases of NADase-positive GAS, which are different in the NADases of NADase-negative strains. Nevertheless, Stevens et al., (2000) rejected an alternative explanation that differences in the amino acid sequence between NADase-positive and NADase-negative isolates could affect structure and function because NADase-negative isolates did not produce an immunoreactive protein or protein fragment. Instead, they proposed that the absence of NADase activity could be explained at the transcriptional level. However, the nga promoter regions of NADase-positive and NADase-negative isolates were identical. Thus, the mechanism is still obscure.
In this study, we investigated the prevalence of NADase activity among clinical isolates of GAS in Japan. Our results provide insights into the mechanism responsible for the variable NADase levels in NADase-negative and NADase-positive isolates as well as in GAS isolates with low to high NADase activity. In addition, we investigated NADase activity of streptococcal strains other than GAS.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Suvorov & Ferretti, 1996). Subspecies of Streptococcus dysgalactiae were identifieded by using the Streptogram kit (Wako). Streptococcal strains were cultured in brain heart infusion (Eiken E-MC62, Japan) supplemented with 0.3 % yeast extract (BHI-Y) broth unless otherwise indicated.
Quantification of NADase activity in bacterial supernatant.
NADase activity was determined by the method of Stevens et al. (2000) with some modifications. Bacteria-free supernatant from 18 h cultures of streptococcal strains was obtained by centrifugation at 15 000 r.p.m. (16 000 g) for 3 min at room temperature. The bacterial supernatant was serially diluted in BHI-Y broth, and the resulting 90 µl samples along with 10 µl β-NAD (2.65 mg per ml–1 water; Sigma) were added to each well of a 96-well plate and incubated at 37 °C in the dark. After 60 min, 35 µl 5 M NaOH was added to stop the reaction. The plates were then placed in the dark for 1 h at room temperature. Fluorescence was detected by using a micro-plate reader (340 nm wavelength, Spectra Max 340, Molecular Devices). Wells that contained known amounts of substrate alone were used to make a standard curve. The amount of residual β-NAD was determined by comparison to the standard curve. NADase activity was demonstrated to be due to Nga by dose-dependent inhibition of activity with purified His-tagged IFS (Nga chaperone) and by the very low level of NADase activity in two nga mutants (GT01
nga and 1529nga, 0.49±0.13 U and 0.66±0.06 U, respectively).
Construction of GST–Nga fusion protein and derivatives.
All PCRs for plasmid construction were performed with Pyrobest DNA polymerase (Takara), which generates blunt-ended fragments. Phosphorylation of 5'-terminal PCR products was achieved with T4 polynucleotide kinase (Takara). The primers used are listed in Table 1. The plasmids for mutant GST–Nga production were sequenced to confirm the intended mutations.
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The ngaGT01-ifs gene was amplified by PCR using the primers nga-n1Bam and IFS-R(EcoRI) and cloned into pGEX-4T-1 to yield pGST-NgaGT01(IFS) encoding a GST–NgaGT01 fusion protein and IFS. Oligonucleotide IFS-R(EcoRI) contained a restriction site for EcoRI (shown in bold type in the primer sequence).
To construct a plasmid encoding GST–NgaGT0138–303 fusion protein, inverse PCR with primers ngac3 and GTnga(BamHI)F1291 was performed to delete the region encoding Nga38–303 from pGST–NgaGT01(IFS). The amplification product was digested with BamHI and self-ligated. Construction of a plasmid encoding GST–NgaGT0138–166 fusion protein was attempted by using a similar technique, except that primer GTnga(BamHI)F871 was used instead of GTnga(BamHI)F1291. The plasmid encoding GST–NgaGT01143–303 fusion protein was constructed with primers ngac3 and GTnga(BamHI)F1291 by using the same strategy, except that the amplification product was self-ligated without BamHI digestion. During the construction of this plasmid, GST–NgaGT01143–451 was accidentally constructed by unexpected degradation (5'-CAAAAAA....ATCGAAGAAG-3') of the PCR product. Degradation of the terminal nucleotide caused a frame-shift which deleted Nga143–451 and added additional six residues (I-I-R-N-V-K).
To construct the plasmid encoding GST–NgaGT01G330D, inverse PCR with primers PngaG330D-F and PngaG330-R was performed to substitute the corresponding glycine of GST–NgaGT01 encoded on pGST–NgaGT01(IFS) with aspartic acid. The amplification product was self-ligated. Oligonucleotide PngaG330D-F contains a point mutation which results in the G330D substitution (shown in bold type in the primer sequence). During this operation, GST–NgaGT01330–451 was accidentally constructed. Mutational change of the nucleotide sequence GGT GTC (encoding Gly330 and Val331) to nucleotide sequence GTA TGT CGA TGA (encoding Val330, Cys331, Arg332 and a stop codon) caused a frame-shift which resulted in the loss of Nga330–451 (the changed nucleotides are shown in bold type).
Construction of the plasmid encoding GST–NgaGT01MQDR was attempted using inverse PCR with primers PdeltaMQDR-F and PdeltaMQDR-R or primers deltaMQDR2 F and PdeltaMQDR2 R to delete the region encoding the second or the first MQDR sequence from pGST-Nga GT01(IFS), respectively. The amplification product was self-ligated. One of the resulting clones possessed a spontaneous mutation changing the codon 442 (AAA) of the nga gene to a stop codon (TAA). This construct was named GST-NgaGT01MQDRMQDR (see Results for details).
To construct a plasmid encoding revertant GST–NgaGT01(IFS), inverse PCR with primers GTngaG330wt-F and PngaG330-R was performed to substitute the corresponding Asp of GST–NgaGT01G330D, encoded on pGST-NgaGT01G330D(IFS), with Gly. The amplification product was self-ligated. The oligonucleotide GTngaG330wt-F contains a point mutation to cause the D330G substitution (shown in bold type in the primer sequence).
In addition to sequencing all coding region of nga genes, the plasmid constructs were verified by using SDS-PAGE to confirm that a protein of the expected size was IPTG-dependently induced in Escherichia coli cells carrying the corresponding construct, but not in those carrying the vector control. During this verification, IPTG-inducible expression of the downstream ifs gene was not observed, although all of the plasmids except for pGST-NgaGT01T377K and pGST-NgaSF370 carry the ifs gene. This is consistent with the finding that IFS was not co-purified with the NADase in the following purification step.
Purification of the recombinant NADase proteins.
The series of GST–Nga fusion proteins were induced and purified as described previously (Tatsuno et al., 2006), with the following modifications. To induce GST–Nga fusion proteins, 0.5 mM IPTG was added to an exponential--phase culture of E. coli JM109 or DH5
carrying a construct encoding the fusion protein and shaken for 90 min at 30 °C. The GST–Nga fusion proteins were purified by using a glutathione Sepharose 4B (MicroSpin) GST purification module (GE Healthcare) according to the manufacturer's instructions. A 12 ml aliquot of the liquid culture was transferred to a centrifuge tube and centrifuged to sediment the cells. The cell pellet was resuspended in 600 µl ice cold 1x PBS. A 3 µl volume of 20 mg ml–1 lysozyme solution in water was added to the cell suspension and incubated at room temperature for 5 min. After 10 freeze/thaw cycles, insoluble material was removed by spinning at full speed (16 000 g) for 10 min. The supernatant was added to the glutathione Sepharose 4B MicroSpin column and mixed gently at room temperature for 7 min. After spinning in a microcentrifuge for 1 min at 735 g, the pellet was washed twice with 400 µl 1x PBS. For elution, a total of 450 µl (three repeated elutions with 150 µl) of glutathione elution buffer was added to the column and incubated at room temperature for 7 min per elution. Characterization by SDS-PAGE confirmed that the IPTG-dependently induced recombinant NADase protein (GST–Nga) and the variants described above were purified as essentially single bands.
Quantification of NADase activity of purified recombinant Nga proteins.
NADase activity was determined as described above, with the following modifications. Purified protein was serially diluted with PBS with or without reduced glutathione, which was used for elution. Activities of bead-bound and eluted GST–Nga were essentially the same. The quantities of protein were determined using a standard curve made with BSA.
Identification of the nga gene.
In order to investigate distribution of the nga gene, PCR, using primers ngaGT-n1Nhe and nga-C4Xho, was performed.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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. In the assay, GAS strain SF370, a known NADase-negative strain, was used as a negative control (Stevens et al., 2000). The proportion of isolates with NADase activity collected between 1989 and 1997 was increased compared with isolates obtained before 1989. Isolates collected between 1998 and 2006 showed a similar distribution of NADase activity types to those collected over the period 1989–1997.
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), whereas the ‘high-activity’ group showed approximately 40–100 units (shown as ‘++’ in Table 2). Thus, the strains were divided into three groups based on activity: low-activity, high-activity and no activity (undetectable activity).
In order to determine the relation between the enzymic activity of Nga and the amino acid sequence, the nga genes of two representative strains (GT01 and 1529) with high (60.9±9.2 U) and low levels (3.4±0.7 U) of NADase activity, respectively, were sequenced. The DNA and protein sequences were identical (data not shown and Fig. 1, respectively). Furthermore five additional nga genes, three from high-activity strains (K2, AP04 and MDMH) and two from low-activity strains (MDN and MDYK) had the same nucleotide and amino acid sequences (data not shown and Fig. 1, respectively). These data indicate that the differences in NADase activity among these seven strains cannot be attributed to differences in NADase protein sequence.
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). The nga genes from strains C242, C1061 and C1236, all isolated before 1989 in Japan and belonging to the ‘no activity’ group, were also sequenced. These genes had the same sequence as SF370 (Fig. 1). Therefore, it is possible that the absence of NADase activity in these four strains is caused by the Nga amino acid sequences.
Cloning of the nga gene
To further characterize the relation between NADase activity and the amino acid sequence, we attempted to clone the nga gene into the expression vector pGEX4T-1, which creates a GST–Nga fusion. As shown in Fig. 2, the nga gene from strain SF370, which is negative for NADase activity, was easily cloned to create GST–NgaSF370. On the other hand, we were unable to successfully clone nga from the NADase-positive strain GT01. All resulting nga constructs possessed mutations in the C-terminal region of nga despite the use of a tightly regulated expression system (data not shown). While most mutations created stop codons or frame-shifts, we successfully obtained two clones with mutations causing the amino-acid substitution T377K or S270P. E. coli JM109 carrying a cloned GST–NgaGT01S270P showed slow growth, indicating that the recombinant protein is toxic to the host bacterium. JM109 carrying GST–NgaGT01T377K did not show delayed growth, suggesting that the T377K mutation in the C-terminal region reduced the toxic effect of NADase activity. Therefore, the C-terminal region of Nga might be involved in NADase activity.
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). We were able to clone nga from strain GT01 in combination with the ifs gene to create GST–NgaGT01 (see Methods for details).
Absence of activity in GST–Nga SF370
GST–NgaGT01 and GST–NgaSF370 were purified and NADase activity was measured. As shown in Fig. 2, GST–NgaGT01 had significantly higher activity than GST–NgaSF370, suggesting that nga of SF370 encodes an inactive form of Nga.
To address the reason why NgaSF370 is enzymically inactive, deduced amino acid sequences of NgaSF370 and NgaGT01 were compared. As shown in Fig. 1, ten differences were observed (NADase-negative to NADase-positive): A99V, H103R, R136G, I195M, I199L, V281L, K289R, D330G, V374I and a MQDR repeat at the C terminus (indicated by bold type in Fig. 1). Among them, the most dramatic differences are at residue, 136 and 330, and the MQDR repeat (Fig. 1). To investigate whether any of these three differences were important for activity we attempted to determine the effects of deleting these regions. Firstly, we attempted to construct deletion constructs GST–NgaGT0138–303 and GST–NgaGT0138–166. GST–NgaGT0138–303 was easily constructed, but we were unable to obtain GST–NgaGT0138–166. This result provided two insights. (1) The C-terminal region (amino acids 167–451) retains the toxic effect conferred by NADase activity. Therefore, amino acid 136 was inferred to be a less important candidate than the two others; (2) IFS is not able to repress the toxic effect of NgaGT01 lacking the N-terminal region (residues 38–166). Therefore, IFS may interact with the N-terminal region of Nga, although we cannot rule out the possibilities that IFS may interact with both N-terminal and C-terminal regions of Nga, and that there are multiple factors that could affect the growth of E. coli besides NADase.
To investigate the remaining two candidates, we attempted to construct GST–NgaGT01MQDR and GST–NgaGT01G330D, but only the latter was successfully constructed. Surprisingly, the substitution of Gly330 with Asp was sufficient to reduce the activity from 50.28 U to 0.27 U. When Asp330 of GST–NgaGT01G330D was changed back to the original Gly, the resultant recombinant protein had activity similar to GST–NgaGT01 (Fig. 2). Thus, absence of activity in NgaSF370 might be attributed to the alteration at the amino acid 330.
We were unable to obtain the GST–NgaGT01MQDR clone. We observed that the plasmid construct was unable to transform E. coli, suggesting that GST–NgaGT01MQDR retains the toxic effect conferred by NADase activity.
The region responsible for NADase activity
As described in the previous section, GST–Nga38–303, despite lacking the hypothetical IFS binding site, was easily constructed, suggesting that the recombinant protein has low activity. As expected, the recombinant showed no detectable NADase activity (1.52±2.38 U). In addition to our suggestion that the C-terminal region of Nga is involved in the activity, this result suggests that the middle portion also plays a role.
Furthermore, NADase activity of other GST–Nga fusion proteins, GST–Nga143–451, GST–Nga143–303, GST–Nga330–451 and GST–NgaGT01T377K, which have either deletions or mutations in the middle and/or C-terminal region, all had reduced activity (Fig. 2). These results are consistent with our speculation that the C-terminal region of Nga is important for NADase activity.
Nga of other streptococcal strains
Kimoto et al. (2005) demonstrated that the group C streptococcal strain H46A has an nga gene. Therefore, we investigated whether other non-group A streptococcal strains have NADase activity. Most of the 25 strains we tested from STSS patients had detectable NADase activity (Table 3). In addition, most GGS, but not group B streptococcus (GBS) strains that we tested had detectable NADase activity.
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and Table 3. Interestingly, every sequence had only a single MQDR sequence at the C-terminal end, suggesting that the duplicate MQDR in NgaGT01 is not critical for enzymic activity.
Deletion of the first MQDR repeat
With regard to the reason why deletion of MQDR elicited loss of IFS effect, we noticed that the region encoding the MQDR sequence overlaps with a potential ribosome-binding site and that the tandem MQDR sequences have synonymous alterations to each other. Deletion of the second MQDR changes the predicted RBS sequence for nga (Fig. 3). The change might contribute to reduced expression of ifs, as well as nga. Therefore we planned to instead delete the first MQDR repeat and leave the second one intact. As expected, GST–NgaMQDR was easily constructed and did not display reduced activity relative to GST–NgaGT01 (Fig. 2). In addition, GST–NgaMQDRMQDR lacking both MQDR repeats also had the same level of activity as GST–NgaGT01 (see Fig. 3 for details of construction).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). This indicates that the increase in NADase-positive strains before 1997 in the United States might not be only a regional trend. Secondly, it has been approximately 10 years since the landmark report using the isolates from the United States; therefore it is valuable to investigate more recent isolates. We found that the trend towards high prevalence of NADase-positive strains is continuing in Japan. It would be interesting to investigate whether this phenomenon is occurring worldwide. There are some interesting genotypic changes from the older strains isolated before 1989 compared to the more recent strains (T. Hasegawa, unpublished data). For example, all of the older strains tested showed a distinctly different pattern after pulsed-field gel electrophoresis compared with all of the recent strains tested.
The strains belonging to the ‘high activity’ group showed higher levels of nga mRNA than the strains of the ‘low activity’ group (T. Hasegawa, unpublished results). Interestingly, it has been reported that the secreted protease SpeB can degrade Nga (Aziz et al., 2004). The amount of secreted SpeB in strains from the ‘low activity’ group was indeed greater than that in strains from the ‘high activity’ group (T. Hasegawa, unpublished results). Therefore, differences in the activities of Nga might involve post-translational regulation in addition to regulation at the transcriptional level.
While we were preparing this manuscript, important information regarding the region of Nga responsible for the NADase activity was published (Ghosh & Caparon, 2006). The result indicated that the enzymic domain of Nga lies within its C-terminal 261 amino-acid residues, essentially consistent with our findings. It should be noted that the previous conclusion was confirmed by our experiments with purified proteins.
Five non-group A streptococcal strains whose nga genes were not detected by PCR analysis showed NADase activity of under one unit (Table 3). Therefore these strains were classified as activity-minus (–), based on the criteria described in Table 2. However, while the strains classified as minus in Table 2 clearly lacked activity (e.g. strain SF370, –0.44±0.8 U; medium only, 0.002±0.22 U), the strains classified as minus in Table 3 had activities significantly higher than zero, even strain NC5, which had the lowest activity (0.24±0.19).
We could not detect NADase in group B streptococci, although the tested strains were isolated from patients with toxic shock syndrome. It would be interesting to determine what phenotype group B streptococci have in the mouse model of STSS. In the mouse model, Nga is important for enabling group A streptococci to cause invasive disease (Bricker et al., 2005). In that previous study, the M-type 3 strain was used, and after subcutaneous inoculation with 108 c.f.u. 20 % of the female ICR mice were dead within a week, whereas the nga mutant caused 0 % death. In very similar experiments, infection with GT01, 1529 and SF370 produced levels of mortality in an NADase-activity-dependent manner (I. Tatsuno and others, unpublished results). In contrast, mice inoculated with GT01nga did not die. In addition, intraperitoneal inoculation of the purified His-tagged IFS protein partially suppressed the virulence of strain GT01 (I. Tatsuno and others, unpublished results).
A survey of nga genes of clinical isolates encoding either Asp or Gly at amino acid 330 could be useful for epidemiological studies. In such studies, assay conditions usually do not represent in vivo conditions. Even if a clinical isolate was identified as NADase-negative under in vitro conditions, if the isolate encodes an active form of Nga, it could display nga-dependent NADase activity in vivo, during infection.
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ACKNOWLEDGEMENTS |
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Edited by: T. Msadek
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Received 6 May 2007;
revised 9 July 2007;
accepted 18 August 2007.
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