Pathogenesis Of Streptococcal Toxic Shock Syndrome Research Articles

Simultaneous isolation of emm89-type Streptococcus pyogenes strains with a wild-type or mutated covS gene from a single streptococcal toxic shock syndrome patient

Streptococcal toxic shock syndrome (STSS) is a re-emerging infectious disease in many developed countries. Recent studies have suggested that mutations in CovRS, a two-component regulatory system in Streptococcus pyogenes, play important roles in the pathogenesis of STSS. However, in vivo evidence of the significance of CovRS in human infections has not been fully demonstrated. We investigated five S. pyogenes strains isolated simultaneously from the pharynx, sputum, knee joint, cerebrospinal fluid and blood of a single STSS patient. All were emm89-type strains, and multilocus sequence typing (MLST) analysis revealed that the strains of pharynx and blood were isogenic. The growth rates of the strains from pharynx and sputum were faster than those of the other strains. Protein profiles of the culture supernatants of strains from the pharynx and sputum were also different from those of the other strains. Sequence analyses revealed that strains from the knee joint, cerebrospinal fluid and blood contained a single nucleotide difference in the covS coding region, resulting in one amino acid change, compared with the other strains. Introduction of a plasmid containing the covS gene from the pharynx strain to the blood strain increased the production of SpeB protein. This suggests that the one amino acid alteration in CovS was relevant to pathogenesis. This report supports the idea that mutated CovS plays important roles in vivo in the dissemination of S. pyogenes from the upper respiratory tract of human to aseptic tissues such as blood and cerebrospinal fluid.

The defensive role of interferon-γ-producing immature myeloid cells in severe invasive group A Streptococcus infections (118.7)

Abstract Streptococcus pyogenes (group A Streptococcus; GAS) is one of the most versatile bacteria among human pathogens. Non-invasive GAS infections can cause common diseases, such as pharyngitis and impetigo. Whereas, severe invasive GAS infections can lead to rapid progressive and life-threatening manifestations, including sepsis, necrotizing fasciitis, and streptococcal toxic shock syndrome (STSS). Although GAS-derived superantigens activate T cells to release excessive amounts of cytokines which are considered to participate in the pathogenesis of STSS following severe invasive GAS infections, it remains unclear which factors are protective against such infections and which cell population is the source of them. Here we show that mice infected with severe invasive GAS isolates, but not with non-invasive GAS isolates, exhibit high concentrations of plasma interferon (IFN)-γ during the early stage of infection. IFN-γ is necessary to protect mice, and is produced by a novel population of granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent immature myeloid cells with ring-shaped nuclei (IFN-γ-producing immature myeloid cells; γIMCs). These γIMCs express monocyte and granulocyte markers, and also produce nitric oxide. The adoptive transfer of γIMCs ameliorates infection in wild-type and IFN-γ-deficient mice. Our results indicate that γIMCs have a defensive role during the early stage of severe invasive GAS infections.

Highly Frequent Mutations in Negative Regulators of Multiple Virulence Genes in Group A Streptococcal Toxic Shock Syndrome Isolates

Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock and multiorgan failure; it has a high mortality rate. Although a number of studies have attempted to determine the crucial factors behind the onset of STSS, the responsible genes in group A Streptococcus have not been clarified. We previously reported that mutations of csrS/csrR genes, a two-component negative regulator system for multiple virulence genes of Streptococcus pyogenes, are found among the isolates from STSS patients. In the present study, mutations of another negative regulator, rgg, were also found in clinical isolates of STSS patients. The rgg mutants from STSS clinical isolates enhanced lethality and impaired various organs in the mouse models, similar to the csrS mutants, and precluded their being killed by human neutrophils, mainly due to an overproduction of SLO. When we assessed the mutation frequency of csrS, csrR, and rgg genes among S. pyogenes isolates from STSS (164 isolates) and non-invasive infections (59 isolates), 57.3% of the STSS isolates had mutations of one or more genes among three genes, while isolates from patients with non-invasive disease had significantly fewer mutations in these genes (1.7%). The results of the present study suggest that mutations in the negative regulators csrS/csrR and rgg of S. pyogenes are crucial factors in the pathogenesis of STSS, as they lead to the overproduction of multiple virulence factors.

Epidemiological study on Streptococcus pyogenes strains isolated from the patients with streptococcal toxic shock syndrome (STSS) in Japan in 1992-2001

To investigate clinical and microbiological features of streptococcal toxic shock syndrome (STSS), clinical, epidemiological, and bacteriological data obtained from 250 patients between 1992 and 2001 were analyzed. Among these 250 cases, 16 cases were excluded from the study because the causative microorganism were not Streptococcus pyogenes. 234 strains of S. pyogenes obtained from the aforementioned 234 cases were tested for T-type by a serological method, and for streptococcal pyrogenic exotoxin (SPE) by in vitro productivity of the toxin as well as molecular genetic methods. The number of patients was 141 (56.4%) for males, and 107 (42.8%) for females. The highest frequency of STSS was observed in those patients in their sixties in both sexes. The overall mortality rate was 43.2%. The mortality rate for male was 36.9%, and 52.3% for female. Bacteriological studies revealed that most common T types were T1 and T3. These strains consisted 54.3% of the strains collected. Among strains of T1 type, 98.8% possessed genes of spe A, and 46.1% were shown to produce SPE A in vitro. Among strains of T3 type, 82.9% possessed spe A gene, and all of these strains were shown to produce the toxin in vitro. It is concluded that certain strains of S. pyogenes, such as those with T1, or T3 type, and those with spe A gene or in vitro production of SPE A, are the most frequent cause of STSS. Although infections caused by such bacteria are quite common, STSS rarely occurs in most such patients. Additional factors, such as host factors, may play a crucial role in the pathogenesis of STSS.

Novel superantigens from streptococcal toxic shock syndrome Streptococcus pyogenes isolates.

The incidence of severe invasive group A streptococcal infections (GAS) and streptococcal toxic shock syndrome (STSS) continues to rise (1), but the reason for this impressive change in epidemiology and clinical manifestation of GAS infections remains a mystery. Streptococcal superantigens (SAgs) have been implicated in the pathogenesis of STSS, but no single SAg can be directly associated with disease (reviewed in 2). A recent outbreak of severe GAS infections in Canada since November 1994 has led to the identification of 95 patients with invasive GAS infections or STSS. These invasive cases could be classified into severe and nonsevere invasive disease based on the clinical symptoms. The severe cases included patients with STSS and necrotizing fasciitis whereas the nonsevere cases were those with no sign of hypotension, organ failure, deep soft tissue involvement or shock. In this study we examined the distribution of genes encoding known streptococcal pyrogenic exotoxins (Spes), which belong to the family of microbial superantigens, among isolates from severe and nonsevere disease. In addition, we investigated the pattern of SAg production by GAS strains isolated from these patients. We report that invasive strains of S. pyogenes produce a number of known Spes as well as novel SAgs that remain to be fully characterized.

Intravenous Immune Globulin Has Effects on Superantigen-Induced Cytokine Synthesis

Increased incidences of invasive group A streptococcal infections occurred in the Western Society in the 1980s, and the number of streptococcal toxic shock syndrome (STSS) cases continue to rise. Among the hypotheses entertained to explain the pathogenesis of STSS has been the concept that streptococcal superantigens (Sags), including streptococcal pyrogenic exotoxins (SPEs), can trigger potent inflammatory responses and release of cytokines of TH 1 type (TNF-oc, IL-1 IFN-γ and TNF-β). These may mediate tissue damage, organ failure, and shock.Pooled human immune globulin G (IgG) preparations for intravenous administration (ivIgG) have been used in many inflammatory conditions due to their immunomodulatory potential. The effector mechanisms are incompletely understood. This study dealt with the effects of ivIgG on cytokine production in vitro. Cytokine synthesis was identified at the single-cell level using cytokine-specific monoclonal antibodies (mAb) and indirect immunocytochemical techniques. The super-antigen streptococcal Pyrogenic exotoxin-A (SPE-A) induced vigorous cell activation and extensive cytokine synthesis. ivIgG was added either at the beginning or 24 h after the initiation of cultures of peripheral blood mononuclear cells (PBMNC) in order to elucidate the importance of direct toxin neutralization. Addition of IVlg (6 mg/ml) from the beginning of cultures induced a strong reduction of blast transformation and an almost complete inhibition of lymphokine production, in particular of IFN-γ and TNF-β. Supplementation of ivIgG 24 h after initiation of cultures also led to a significant decrease