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PubMed2004

Low antibody levels against cell wall-attached proteins of Streptococcus pyogenes predispose for severe invasive disease.

Acute-phase serum samples from 70 patients with group A streptococcal (GAS) invasive disease were analyzed for IgG antibodies against 6 recently characterized GAS virulence factors (SclA, SclB, GRAB, MtsA, EndoS, and IdeS) and SpeB. Antibody levels against the cell wall-attached GAS antigens SclA, SclB, and GRAB were significantly lower in patients with severe invasive disease (streptococcal toxic shock syndrome [STSS] and/or necrotizing fasciitis [NF]; n=35), compared with levels in patients with nonsevere GAS bacteremia (n=35). Among patients with severe invasive disease, significantly lower antibody levels against GRAB were found in patients with STSS (n=10) than in patients with NF (n=17). Antibody levels against SpeB in patients with severe bacteremia were similar to those in patients with nonsevere bacteremia, and levels in patients with STSS were similar to those in patients with NF. The data indicate that immunity to cell wall-attached proteins may play a role in the protection against severe invasive disease and that antibodies against GRAB may be of importance in the pathogenesis of STSS.

Antibodies, Bacterial↗

PubMed2000

Changed expression of leukocyte adhesion molecules and increased production of reactive oxygen species caused by Streptococcus pyogenes in human whole blood.

To elucidate the innate immune responses to group A streptococci (GAS) important in the pathophysiology of sepsis, flow cytometric techniques were applied to study the effects of live and heat-inactivated GAS, including their particulate and soluble components, on the expression of leukocyte adhesion molecules CD11b (Mac-1) and CD62L (L-selectin), and leukocyte production of reactive oxygen species (ROS) in human whole blood. GAS caused marked time- and concentration-dependent increases in CD11b and ROS, while CD62L was downregulated. Live and heat-inactivated GAS induced similar changes in leukocyte adhesion molecules, whereas ROS production induced by heat-inactivated GAS (and its particulate fraction) was 4 (2.5)-fold higher than with live GAS. Leukocyte nitric oxide production (24 h) was not enhanced. Although GAS proved a more potent inducer of ROS production, leukocyte responses to GAS were similar to those reported for lipolysaccharides, indicating that Gram-positive and Gram-negative bacteria activate common pathways in the inflammatory response. High ROS production may contribute to tissue damage caused by GAS.

Arginine↗

PubMed2005

Vascular dysfunction and ischemic destruction of tissue in Streptococcus pyogenes infection: the role of streptolysin O-induced platelet/neutrophil complexes.

Rapid tissue destruction in group A streptococcal (GAS) necrotizing fasciitis/myonecrosis often necessitates extensive debridement to ensure survival. The mechanisms responsible for this fulminant process remain unknown; we hypothesized that toxin-induced ischemia contributes to necrosis. In a rat model, Doppler flowmetry was used to measure local blood flow at the site of the intramuscular injection of exotoxins from an invasive M-type 1 GAS, which caused a rapid, dose-dependent decrease in perfusion that was irreversible at the highest toxin concentration tested. Videomicroscopic results revealed that blood flow was impeded by occlusive intravascular cellular aggregates. Flow-cytometric results confirmed that GAS toxins induced the coaggregation of platelets and neutrophils, that this activity was attributable to streptolysin O, and that platelet/neutrophil complex formation was largely mediated by platelet P-selectin (CD62P). Strategies that target platelet adherence molecules may prevent vascular occlusion, maintain tissue viability, and reduce the need for amputation in necrotizing GAS infections.

Animals↗

PubMed2006

Conformation and stability of the Streptococcus pyogenes pSM19035-encoded site-specific beta recombinase, and identification of a folding intermediate.

Solution properties of beta recombinase were studied by circular dichroism and fluorescence spectroscopy, size exclusion chromatography, analytical ultracentrifugation, denaturant-induced unfolding and thermal unfolding experiments. In high ionic strength buffer (1 M NaCl) beta recombinase forms mainly dimers, and strongly tends to aggregate at ionic strength lower than 0.3 M NaCl. Urea and guanidinium chloride denaturants unfold beta recombinase in a two-step process. The unfolding curves have bends at approximately 5 M and 2.2 M in urea and guanidinium chloride-containing buffers. Assuming a three-state unfolding model (N2-->2I-->2U), the total free energy change from 1 mol of native dimers to 2 mol of unfolded monomers amounts to deltaG(tot) = 17.9 kcal/mol, with deltaG(N2-->2I) = 4.2 kcal/mol for the first transition and deltaG(I-->U) = 6.9 kcal/mol for the second transition. Using sedimentation-equilibrium analytical ultracentrifugation, the presence of beta recombinase monomers was indicated at 5 M urea, and the urea dependence of the circular dichroism at 222 nm strongly suggests that folded monomers represent the unfolding intermediate.

Bacterial Proteins↗

PubMed1997

Survey of emm gene sequences and T-antigen types from systemic Streptococcus pyogenes infection isolates collected in San Francisco, California; Atlanta, Georgia; and Connecticut in 1994 and 1995.

The variable 5' emm (M-protein gene) sequences and T-antigen types were determined from 340 systemic group A streptococcal (GAS) isolates taken from hospitalized patients in San Francisco, Calif.; Atlanta, Ga.; and Connecticut in 1994 and 1995. Eighty percent of these isolates had emm sequences and T-antigen types in agreement with previously recorded M- and T-antigen associations. Most of the remaining strains either were T nontypeable (11%) or contained emm genes encoding M proteins for which T-antigen associations have not been made (6%). One newly encountered emm gene, designated ST2974, from each of 13 isolates had the T type 8/25/Imp19. Another new emm gene, ST2967, from 8 of 11 isolates was T nontypeable. Six other unique emm gene sequences from seven isolates were encountered. Sequencing of the variable region of the emm gene of GAS isolates (emm typing) is effective for surveying the sequence variability of the M virulence protein, and combined with T typing, emm typing is useful for monitoring GAS strain diversity.

Amino Acid Sequence↗

PubMed1983

ATP-dependent protein kinase-catalyzed phosphorylation of a seryl residue in HPr, a phosphate carrier protein of the phosphotransferase system in Streptococcus pyogenes.

HPr, a phosphate carrier protein of the streptococcal phosphotransferase system, is phosphorylated at the N-1 position of a single histidyl residue in a reaction requiring phosphoenolpyruvate (P-ePrv), Mg2+, and enzyme I (P-ePrv-HPr phosphotransferase, EC2.7.3.9). We demonstrate that in addition to this reaction, a seryl residue within HPr can be phosphorylated in an ATP-dependent process. This reaction is catalyzed by a protein kinase with an approximate Mr of 20,000. In whole cells the kinase activity is stimulated by glucose, whereas in crude extracts the activity is stimulated by glycolytic intermediates such as glucose 6-phosphate, fructose 1,6-diphosphate, and 2-phosphoglycerate. P-(Ser)-HPr cannot transfer its phosphate group via enzyme II to a sugar as does the P-(His)-HPr. Instead, a phosphatase (Mr = 70,000) was found to hydrolyze the phosphate group of P-(Ser)-HPr. The phosphatase reaction is strongly inhibited by the addition of P-ePrv and enzyme I. Protein kinase-catalyzed phosphorylation of the enzyme constituents of the phosphotransferase system in Escherichia coli has also been demonstrated. These observations lead us to suggest that phosphorylation of a seryl residue in HPr is involved in the regulation of sugar transport in the bacteria cell.

Bacterial Proteins↗

PubMed2004

Fate of Streptococcus pyogenes and epithelial cells following internalization.

The fate of GAS and epithelial cells following internalization was determined in this study. HEp-2 cells harbouring intracellular bacteria were treated with antibiotics to kill extracellular adherent bacteria, washed, and the fate of bacteria and epithelial cells was assessed up to 24 h post-infection. In the absence of antibiotics, massive bacterial growth was apparent in the cell medium, accompanied by extensive cell death, suggesting that intracellular bacteria had multiplied and damaged the monolayer. Addition of the internalization inhibitor, cytochalasin D, either pre- or post-internalization prevented bacterial growth and cell injury; post-internalization treatment with chloramphenicol had the same effect. Analysis of three apoptotic markers in HEp-2 cells - chromatin condensation, DNA laddering and translocation of phosphatidylserine onto the cell-surface membrane - indicated that HEp-2 cells underwent apoptosis. Taken together, the data presented here support a model in which internalized bacteria can induce their own externalization into the medium by a process that requires both an intact host-cell cytoskeleton and de novo synthesis of bacterial proteins. Concomitantly, intracellular and, apparently, extracellular free bacteria induce apoptosis through their cytotoxic activity, and release essential nutrients required for their growth.

Anti-Bacterial Agents↗

PubMed1988

Streptococcus pyogenes bacteraemia in Cambridge--a review of 67 episodes.

Sixty-seven episodes of bacteraemia due to Lancefield Group A streptococci occurred in patients admitted to or autopsied at Addenbrooke's Hospital, Cambridge from July 1974 to June 1986. Ninety-two per cent of infections were acquired in the community and 71 per cent of patients were adults. The overall mortality rate was 48 per cent and 15 per cent of cases died at home shortly after the onset of illness. Thirty-eight per cent of the patients had underlying disease and sixty-one per cent of these died compared with 40 per cent of those without underlying disease. Presentation in shock was the major predictor of mortality (79 versus 16 per cent) and was commoner in adults. Clinical features were variable and led to incorrect initial diagnosis in some cases. A localized site of infection was not recognized initially in 37 per cent of cases but the commonest evident site of entry was the skin. Annual incidence varied with age from 0.71 to 4.16/100,000 population and cases were commonest in the young and those over 50. The fulminating onset of community-acquired streptococcal infection in some adults emphasizes the importance of early treatment of suspected cases with penicillins.

Adolescent↗

PubMed1996

Treatment failure in streptococcal pharyngotonsillitis. An attempt to identify penicillin tolerant Streptococcus pyogenes.

Penicillin tolerance in group A streptococci has been suggested to cause treatment failures in pharyngotonsillitis. In the present study, group A streptococci from patients with pharyngotonsillitis, who healed (n = 33) or failed (n = 25) on phenoxymethylpenicillin therapy for 10 days, as well as isolates obtained following the first (n = 25) and second (n = 7) failure were tested for penicillin tolerance by a plate-screening method. For most strains, the survival rate after a 6-h exposure of log-phase bacteria (10(4) CFU) to a phenoxymethylpenicillin concentration of 4 times the minimum inhibitory concentration (MIC) was below 0.1%. Five strains from cases of failure, exhibiting survival rates of 0.2-0.5%, were subjected to time killing kinetic tests with phenoxymethylpenicillin at 12 times the MIC. At 6 h each of the strains from failures showed survival rates below 0.03%. One single group A strain, previously selected in our laboratory, showed a survival rate of 0.4-1.2%, which was close to tolerance as defined. Four streptococcal strains, earlier reported as tolerant, showed survival rates of > 1% but were found to be group G. Penicillin tolerance does not significantly contribute to failures in penicillin therapy of group A streptococcal pharyngotonsillitis, but seems to be a common property of group C and G streptococci.

Colony Count, Microbial↗

PubMed2001

Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in Streptococcus pyogenes.

The amino-terminal hypervariable region (HVR) of streptococcal M protein is required for the ability of this virulence factor to confer phagocytosis resistance. The function of the HVR has remained unknown, but the finding that many HVRs with extremely divergent sequences bind the human complement regulator C4b-binding protein (C4BP) has suggested that this ligand may play a role in phagocytosis resistance. We used the M22 system to study the function of bound C4BP and provide several lines of evidence that C4BP indeed contributes to phagocytosis resistance. First, the ability of anti-HVR antibodies to cause opsonization correlated with their ability to inhibit binding of C4BP. Secondly, a short deletion in the HVR eliminated C4BP binding and also reduced the ability of M22 to confer phagocytosis resistance. Thirdly, the addition of an excess of pure C4BP to a phagocytosis system almost completely blocked the effect of opsonizing anti-HVR antibodies. Together, our data indicate that binding of C4BP to the HVR of M22 plays an important role in phagocytosis resistance, but other properties of M22 also contribute. This study provides the first molecular insight into the mechanisms by which the HVR of an M protein confers phagocytosis resistance.

Amino Acid Sequence↗

PubMed2006

Release of SpeA from Streptococcus pyogenes after exposure to penicillin: dependency on dose and inhibition by clindamycin.

The amount and time course of SpeA release from group A streptococci (GAS) was studied at different starting inoculate after exposure to different doses of penicillin, clindamycin or a combination of the 2. The release was related to the bacterial concentration and killing rate. A clinical GAS strain was exposed to benzylpenicillin, 2 and 1000 x MIC, clindamycin, 2 and 32 x MIC, or combinations of the 2. Samples for viable counts and SpeA analyses were drawn before and after the addition of antibiotics and at 3, 6 and 24 h. The SpeA release was higher at low than at high concentrations of penicillin and the combination (both, p<0.05). The addition of clindamycin to penicillin reduced SpeA production at both concentrations (p<0.01). Most SpeA was released before 3 h, and for penicillin and the combination, the amount correlated to the number of killed bacteria during this period (r=0.50; p<0.05). A positive correlation was found between the inoculum size and the SpeA concentration at time zero (r=0.54; p<0.05). The SpeA concentration was dependent on the initial number of bacteria, the class of antibiotic, the dose of penicillin and the killing rate.

Anti-Bacterial Agents↗

PubMed1997

Streptococcus pyogenes type 5 M protein is an antigen, not a superantigen, for human T cells.

M proteins are coiled-coil dimers expressed on group A streptococcal cell surfaces. They have an important role in host antistreptococcal immunity and in poststreptococcal autoimmune sequelae. Controversy has arisen regarding whether type 5 M proteins are superantigenic for human T cells. To investigate this, we have produced and tested M5 in the form of two novel recombinant proteins. We found no evidence of superantigenicity using either recombinant whole M5 protein (rM5) or recombinant pep M5 protein (rpepM5) to activate peripheral blood mononuclear cells (PBMC) from healthy adult volunteers. Short-term, rM5-specific T-cell lines from different subjects were uniformly self-APC restricted and showed no consistent pattern of TCR V beta usage. A synthetic peptide of M5 residues 217-237 was found to contain epitope(s) recognized by some rM5-specific human T cells. PBMC responses to rM5 and rpepM5 in 3- and 7-day proliferation assays were characteristic of antigenic rather than superantigenic stimulation. We conclude that type 5 M protein activates human T cells as a conventional antigen.

Adult↗

PubMed1999

Characterization of a two-component system in Streptococcus pyogenes which is involved in regulation of hyaluronic acid production.

Hyaluronic acid production by group A streptococci is regulated by transcriptional control. In this study, transposon mutagenesis of an unencapsulated strain yielded an encapsulated mutant. Two genes homologous to sensors and response regulators of bacterial two-component systems were identified downstream of the transposon insertion. Inactivation of the putative sensor gene, csrS, in three different unencapsulated strains yielded encapsulated mutant strains. Electrophoretic mobility shift assays determined factor(s) in a cytoplasmic extract of an unencapsulated group A streptococcal strain was binding to a double-stranded DNA fragment derived from the has operon promoter. In contrast, similarly prepared cytoplasmic extracts from a csrS deletion mutant did not shift the fragment. The putative response regulator, CsrR, was partially purified and was shown to bind the has operon promoter fragment. The affinity and specificity of CsrR for the fragment were increased significantly after incubation with acetyl phosphate. DNase I footprinting determined that the acetyl phosphate-treated CsrR was binding to key sequences in the promoter and the coding region of hasA. Therefore, a two-component system is repressing the production of hyaluronic acid in group A streptococci using a phosphorylation-dependent binding interaction between the response regulator CsrR and the promoter region of the has operon.

Alleles↗

PubMed1992

Erythrogenic toxins A, B and C: occurrence of the genes and exotoxin formation from clinical Streptococcus pyogenes strains associated with streptococcal toxic shock-like syndrome.

We report the study of 53 clinical isolates of group A streptococci, all from patients with streptococcal toxic shock-like syndrome. The strains were analysed for the occurrence of the genes of erythrogenic toxins (pyrogenic exotoxins) types A, B and C and in vitro production of these toxins. In contrast to reports indicating that 85% of the toxic shock-like syndrome-associated isolates contained the erythrogenic toxin A gene, only 58.5% of our strains harboured this gene. The erythrogenic toxin C gene was detected in 22.6% of the isolates. Erythrogenic toxin A and erythrogenic toxin B were produced by 68.7% and 58.3% of the strains containing either gene. For all group A streptococci, irrespective of clinical association, the erythrogenic toxin B gene was detected in all the isolates tested. Thus, it is difficult to define a specific role for erythrogenic toxin B in toxic shock-like syndrome as there was no clear correlation between this disease and the presence of toxin genes. Our results suggest the existence of other pathogenic factor(s) produced by group A streptococci which may stimulate human peripheral T lymphocytes in a manner similar to that of erythrogenic toxins, thus explaining different observations in previous epidemiological genetic studies.

Amino Acid Sequence↗

PubMed1991

Antibody levels and in vitro lymphoproliferative responses to Streptococcus pyogenes erythrogenic toxin A and mitogen of patients with rheumatic fever.

We investigated the in vitro lymphoproliferative responses to a streptococcal mitogen and erythrogenic toxin A of children with acute rheumatic fever (ARF) and patients with chronic rheumatic heart disease (CRHD). Antibody levels to the streptococcal products were also analyzed in the sera of those with ARF or chronic rheumatic heart disease as well as in the sera of children with streptococcal pharyngitis or poststreptococcal glomerulonephritis. Our results demonstrated that the individuals had depressed lymphoproliferative responses during the active stage of rheumatic fever. The depressed responses were not found either to be induced by time-sensitive mitogen-specific suppressor cells or to be related to a dose-response phenomenon. On the other hand, antibody levels to the extracellular mitogens were significantly elevated in the sera of children with ARF compared with the levels in the rest of the groups. The hyperresponsiveness noted among children with ARF was found to be at a quantitative level and was not due to recognition of more epitopes, as determined by Western blotting (immunoblotting). The profile of immune responsiveness in children with ARF to the streptococcal extracellular mitogens is discussed in relation to the pathogenesis of disease.

Adolescent↗

PubMed1984

A bacteriocin produced by certain M-type 49 Streptococcus pyogenes strains when incubated anaerobically.

Bacteriocin production (P)-typing of 75 M-type 49 group-A streptococci obtained from a variety of epidemiological incidents in different countries gave no evidence of production under the usual aerobic test conditions. However, with anaerobic incubation, 28% of the strains gave a pattern of inhibitory activity against the indicator strains which was indistinguishable from that previously attributed to the bacteriocin, streptococcin A-FF22 (SA-FF22). Isolation and partial purification of the M type 49 bacteriocin (SA-M49) by freeze-thaw elution from anaerobically grown lawn cultures, followed by ammonium sulphate precipitation and Sephadex chromatography, showed the activity to be associated with a heat-stable proteinaceous molecule of molecular weight approximately 8000 - properties similar to those of SA-FF22. SA-FF22 and SA-M49 were found to have identical inhibitory spectra including immunity of the producer strains to the inhibitory activity of both the homologous and heterologous bacteriocin preparations. SA-M49 production occurred in some strains of phage subtypes II, III and provisional VI and, since it was a consistent property for all isolates from single outbreaks of infection, it provides a means of discriminating between strains of each of these three phage subtypes. There was no evidence of any increased incidence of SA-M49 production in M-type 49 strains associated with nephritic sequelae.

Anaerobiosis↗

PubMed1995

Isolation and characterization of a mitogen characteristic of group A streptococci (Streptococcus pyogenes).

It has been supposed for many years that group A streptococci may elaborate more than the three well known erythrogenic toxins A, B or C (ETA, ETB, ETC). The analysis of the culture supernatant of streptococcal strain 27297 carrying neither genes for ETA nor ETC revealed mitogenic activity at pH 7.3 in isoelectric focusing. This mitogen of strain 27297 was purified by hydrophobic adsorption to Phenyl-Sepharose following FPLC chromatography on a Mono S column resulting in two proteins with mitogenic activity called AX and BX, respectively. Both differed in only one aminoterminal residue. The mitogenic activity of BX lacking one aminoterminal arginine was found to be about 100 times higher than that of AX. The aminoterminus of BX does not correspond to a predictable cleavage site for signal peptidase. We assume that BX was produced after translation by cleavage of the mature protein or the AX molecule with streptococcal proteinase (ETB) or an arginylaminopeptidase which is detectable on whole cells. The purified proteins BX and AX showed molecular weights of about 27 kDa in SDS electrophoresis and isoelectric points of 8.3 (AX) and 7.3 (BX) in isoelectric focusing, respectively. Both proteins were produced by practically all group A strains tested but not by groups B, C, G or H streptococci. Therefore, AX or BX seem to be proteins characteristic of group A streptococci.

Amino Acid Sequence↗

PubMed2006

Identification of macrolide-resistant clones of Streptococcus pyogenes in Portugal.

Although the overall level of macrolide resistance (27%) has remained stable in Portugal, a rapid inversion in the dominant phenotypes has been noted, with a sharp decrease in the MLS(B) phenotype paralleled by an increase in the M phenotype. To gain further insight into these changes, 325 macrolide-resistant isolates were characterised using a combination of pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The use of Cfr9I, an isoschizomer of SmaI, to digest M phenotype isolates that were refractory to SmaI digestion allowed direct comparison of MLS(B) and M isolates. The results from PFGE and MLST were highly concordant and identified eight major clones, accounting for 92% of the isolates, each of which was associated exclusively with a single macrolide resistance phenotype. Two major clones were found among MLS(B) isolates, characterised by sequence types (ST) 46 (T12/emm22) and ST52 (T28/emm28), whereas clones characterised by ST39 (T4/emm4) and ST28 (T1/emm1) dominated among M isolates. The clone defined by ST52 corresponded to a bacitracin-resistant clone circulating in Europe, and a novel variant expressing other surface antigens (T12/emm22) was detected. The presence of the four major clones has been reported previously in other European countries, suggesting Europe-wide dissemination of a few macrolide-resistant lineages.

Bacitracin↗