STRUCTURE AND FUNCTION OF STREPTOCOCCAL AND STAPHYLOCOCCAL SUPERANTIGENS IN SEPTIC SHOCK

doi:10.1016/S0891-5520(05)70081-7

Infectious Disease Clinics of North America

Volume 13, Issue 2, 1 June 1999, Pages 387-396

https://doi.org/10.1016/S0891-5520(05)70081-7 Get rights and content

The pyrogenic exotoxins of group A streptococci (SPEs) and the enterotoxins of Staphylococcus aureus (SEs) constitute a family of structurally related toxins that also share similar biologic activities.26, 30 They stimulate CD4, CD8, and γδ⁺ T cells by a unique mechanism. These toxins share the ability to bind the β chain variable region (Vβ) elements on the lateral face of the T cell receptor (TCR) and simultaneously bind to the lateral face of the class II major histocompatibility complex (MHC) of antigen-presenting cells (Fig. 1), causing an aberrant proliferation of specific T cell subsets.13, 15, 28 These toxins have been labeled as superantigens,⁶⁸ because they do not interact with the MHC and TCR molecules in the manner of conventional antigens.31, 39 Superantigens have evolved independently over time from different genetic backgrounds, yet share common structural and functional elements.

These bacterial toxins cause a variety of syndromes in humans. The SEs have been implicated in staphylococcal food poisoning⁵⁷ and toxic shock–like syndromes.⁵ The gene sequences and deduced amino acid sequences of at least seven staphylococcal enterotoxins are known: SEA, SEB, SEC, SED, SEE, and SEH.40, 49

The SPEs have been implicated in causing the symptoms of scarlet fever and toxic shock–like syndrome.23, 44, 60 The sequences of three members of this family are known: SPEA, SPEC, and streptococcal superantigen (SSA).17, 48, 66

Toxic shock syndrome toxin (TSST-1) from S. aureus shares similar biologic activity with the SEs and SPEs; however, amino acid sequences of this toxin are significantly different from the latter two classes of toxins.⁹ Structural analysis suggests that, despite the differences in amino acid composition, the overall topology of TSST-1 and the SE/SPE family of toxins is similar.¹

Section snippets

STRUCTURE AND FUNCTION

The molecular structure of SEs and SPEs has been determined by various methods. Reviews concerning the molecular structures are available.40, 52 Molecular evolution studies of the SE/SPE family of toxins suggest that the toxins can be grouped into two main classes.⁶³ All these toxins are highly resistant to denaturation by heat and to proteases. With the exception of TSST-1, they are soluble proteins of approximately 230 amino acids and have a central disulfide loop (TSST-1 has only 194 amino

MITOGENIC ACTIVITY

The cross-linking of TCR with MHC-II molecules by superantigens causes a profound blastogenesis of lymphocytes and antigen-presenting cells. The resulting stimulation of leukocytes leads to a significant increase in cytokine production.

Monocytes stimulated with bacterial superantigens produce the Th1 cytokines IL-2 and IFN-γ and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist.⁴³ T cells activated by superantigen stimulation produce IL-12.³⁷ Whole preparations of peripheral

CLINICAL MANIFESTATIONS

The SEs are named for their ability to induce gastrointestinal illnesses upon oral intake of a few micrograms of the toxin. The clinical effect appears in 2 to 4 hours and is manifested by nausea and diarrhea. These symptoms appear to be caused by leukotrienes and histamine released from mast cells. Additionally, both the staphylococcal and streptococcal exotoxins are implicated in gram-positive shock. Although superantigen-related septic shock appears to be primarily mediated by tumor necrosis

TWO-HIT HYPOTHESIS OF SEPTIC SHOCK

There is increasing evidence that gram-positive infections frequently accompany gram-negative infections in patients with septic shock (see article by Rangel-Frausto, pages 299–312). Exposure to gram-negative endotoxin produces a state of macrophage hyporesponsiveness on subsequent stimulation.³ A similar state is seen with monocytes in septic shock. Our group and others have shown that LPS and superantigens can act synergistically to produce lethal septic shock in animal models.⁵² It is our

THERAPEUTIC MEASURES

The clinical manifestations of shock are complicated and require a variety of supportive measures. These include fluid therapy (assuming adequate renal function), vasoactive agents aimed at maintaining blood pressure, and other supportive measures to maintain homeostasis. Fluid replacement is a simple treatment shown to be quite effective in a rabbit model of toxic shock.³⁵ Additionally, appropriate antibiotics given intravenously are part of current standard therapy.

Therapies directed at the

References (69)

M. Astiz et al.
Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis
J Lab Clin Med
(1996)
L. Björk et al.
Quantification of superantigen induced IFN-γ production by computerised image analysis-inhibition of cytokine production and blast transformation by pooled human IgG
J Immunol Methods
(1994)
J.N. Blankson et al.
The CD28/B7 pathway cosimulates the response of primary murine T cells to superantigens as well as to conventional antigens
Cell Immunol
(1994)
B.L. Kotzin et al.
Superantigens and their potential role in human disease
Adv Immunol
(1993)
T. Krakauer
Cell adhesion molecules are co-receptors for staphylococcal enterotoxin B-induced T-cell activation and cytokine production
Immunol Lett
(1994)
S. Li et al.
Superantigen-mediated proliferation and cytotoxicity of T cells isolated from the inflammatory tissues and peripheral blood of arthritis patients
Clin Immunol Immunopathol
(1996)
C.H. Pontzer et al.
Agonist properties of a microbial superantigen peptide
Biochem Biophys Res Commun
(1993)
R.J. Smith et al.
Dual infections with Staphylococcus aureus and Streptococcus pyogenes causing toxic shock syndrome. Possible synergistic effects of toxic shock syndrome toxin 1 and streptococcal pyrogenic exotoxin C
Diagn Microbiol Infect Dis
(1994)
J.M. Soos et al.
Multiple binding sites on the superantigen, staphylococcal enterotoxin B, imparts versatility in binding to MHC class II molecules
Biochem Biophys Res Commun
(1994)
L. Spero et al.
Biological activities of the peptides of staphylococcal enterotoxin C formed by limited tryptic hydrolysis
J Biol Chem
(1978)

StelmaG.N. et al.

Inactivation of staphylococcal enterotoxin A by chemical modification

Biochem Biophys Res Commun

(1982)

Van den BusscheR.A. et al.

Molecular evolution of the staphylococcal and streptococcal pyrogenic toxin gene family

Mol Phylogenet Evol

(1993)

J.R. Warren et al.

Stabilization of native structure by the closed disulfide loop of staphylococcal enterotoxin B

Biochim Biophys Acta

(1974)

J. White et al.

The V beta-specific superantigen staphylococcal enterotoxin B: Stimulation of mature T cells and clonal deletion in neonatal mice

Cell

(1989)

K.R. Acharya et al.

Structural basis of superantigen action inferred from crystal structure of toxic-shock syndrome toxin-1

Nature

(1994)

J. Andersson et al.

Lymphokine production induced by streptococcal pyrogenic exotoxin-A is selectively down-regulated by pooled human IgG

Eur J Immunol

(1994)

J.D. Bannan et al.

Neutralization of streptococcal pyrogenic exotoxins and staphylococcal enterotoxins by antisera to synthetic peptides representing conserved amino acid motifs

Adv Exp Med Biol

(1997)

M.S. Bergdoll

The staphylococcal enterotoxins—An update

C. Blank et al.

Superantigens and endotoxin synergize in the induction of lethal shock

Eur J Immunol

(1997)

D.A. Blomster-Hautama et al.

The nucleotide and partial amino acid sequence of toxic shock syndrome toxin-1

J Biol Chem

(1986)

G.A. Bohach et al.

Cross-neutralization of staphylococcal and streptococcal pyrogenic toxins by monoclonal and polyclonal antibodies

Infect Immun

(1988)

S. Brocke et al.

Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen

Nature

(1993)

S.K. Chapes et al.

Differential RNA regulation by staphylococcal enterotoxins A and B in murine macrophages

J Leukoc Biol

(1994)

Y. Choi et al.

Interaction of Staphylococcus aureus toxin superantigens with human T cells

Proc Natl Acad Sci U S A

(1989)

C. Edwin et al.

Specificity and cross-reactivity of staphylococcal enterotoxin A monoclonal antibodies with enterotoxins B, C1, D, and E

Appl Environ Microbiol

(1986)

B. Fleischer et al.

T cell stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for major histocompatibility complex class II molecules on accessory or target cells

J Exp Med

(1988)

R. Goldbach-Mansky et al.

A co-stimulatory role for CD28 in the activation of CD4+ T lymphocytes by staphylococcal enterotoxin B

Int Immunol

(1992)

S.C. Goshorn et al.

Nucleotide sequence of streptococcal exotoxin type C

Infect Immun

(1988)

N.D. Griggs et al.

Mapping of multiple binding domains of the superantigen staphylococcal enterotoxin A for HLA

J Immunol

(1992)

D. Grossman et al.

Dissociation of the stimulatory activities of staphylococcal enterotoxins for T cells and monocytes

J Exp Med

(1990)

D. Grossman et al.

Mutation of the disulfide loop in staphylococcal enterotoxin A. Consequences for T cell recognition

J Immunol

(1991)

S.P. Hackett et al.

Superantigens associated with staphylococcal and streptococcal toxic shock syndrome are potent inducers of tumor necrosis factor beta synthesis

J Infect Dis

(1993)

U.F. Hartwig et al.

Mutations affecting MHC class II binding of the superantigen streptococcal erythrogenic toxin A

Int Immunol

(1993)

A.R. Hauser et al.

Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock–like syndrome

J Clin Microbiol

(1991)

Cited by (39)

Disseminated Infections: A Clinical Overview
2014, Molecular Medical Microbiology
The ability of microorganisms to cause infection is governed by multiple different factors – some linked to the microorganisms itself and others to the host or environment. In this chapter we explore some of these factors and provide an overview of disseminated infections examining some important manifestations such as toxic shock syndrome and sepsis as well as examining some of molecular aspects including host receptors and bacterial antigens. A brief discussion will also follow about disseminated infections in specific populations such as neonates and the immunosuppressed.
Staphylococcus aureus toxins - Their functions and genetics
2014, Infection, Genetics and Evolution
Citation Excerpt :
In animal models, SAgs and LPS, a major component of the outer membrane of Gram-negative bacteria and highly potent stimulator of the innate immune system, most effectively synergize in the induction of lethal shock (Blank et al., 1997; Schlievert, 1982). This observation prompted the development of the two-hit model of septic shock (Bannan et al., 1999), which was later generalized by Holtfreter and Bröker: A first hit by SAgs or other potent T cell stimuli is potentiated by a second hit by pathogen-associated molecular patterns (PAMPs), which activate the innate immune system. This sequence of events culminates in a dramatic, often lethal activation of the whole immune system (Holtfreter and Bröker, 2005).
The outcome of encounters between Staphylococcus (S.) aureus and its human host ranges from life-threatening infection through allergic reactions to symptom-free colonization. The pan-genome of this bacterial species encodes numerous toxins, known or strongly suspected to cause specific diseases or symptoms. Three toxin families are in the focus of this review, namely (i) pore-forming toxins, (ii) exfoliative toxins and (iii) superantigens. The majority of toxin-encoding genes are located on mobile genetic elements (MGEs), resulting in a pronounced heterogeneity in the endowment with toxin genes of individual S. aureus strains. Recent population genomic analysis have provided a framework for an improved understanding of the temporal and spatial scales of the motility of MGEs and their associated toxin genes. The distribution of toxin genes among clonal lineages within the species S. aureus is not random, and phylogenetic (sub-)lineages within clonal complexes feature characteristic toxin signatures. When studying pathogenesis, this lineage association, which is caused by the clonal nature of S. aureus makes it difficult to discriminate effects of specific toxins from contributions of the genetic background and/or other associated genetic factors.
Antibodies to highly conserved peptide sequence of staphylococcal and streptococcal superantigens in Kawasaki disease
2004, Experimental and Molecular Pathology
Superantigen-mediated disease such as toxic shock syndrome is seen in patients who have a weak antibody response to the antigen toxic shock syndrome toxin 1 (TSST-1). We hypothesized that there may be deficiency in antibody production to staphylococcal and streptococcal toxins in Kawasaki disease (KD) children. A peptide was constructed from the homologous portion of the staphylococcal enterotoxins (SE) and streptococcal pyrogenic enterotoxins (SPE), and antibodies to the peptide were made. The anti-peptide antibody immunoblotted several of the SE toxins and SPE toxins. Presence of the peptide antibodies was investigated via ELISA in the sera of acute KD (n = 30), convalescent KD (n = 12), control adults (n = 10), and children (n = 19). The mean anti-peptide antibodies were indistinguishable between control children and KD before treatment with immunoglobulin (P = 0.7) but rose significantly after therapy (P < 0.01). The adults had significantly higher antibodies than the KD, both acute and late (P < 0.0001) and the control children (P < 0.0001). Thus, KD patients do not have a defective serological response against toxins such as SPE/SE/TSST-1. Normal children have significantly lower antitoxin antibody levels to the toxins compared to the adults.
Simultaneous activation of apoptosis and inflammation in pathogenesis of septic shock: A hypothesis
2003, FEBS Letters
Sepsis, a widely prevalent disease with increasing morbidity and mortality, is thought to result from uncontrolled inflammatory responses to microbial infection and/or components. However, failure of several experimental anti-inflammatory therapies has necessitated re-evaluation of the paradigm underlying the pathogenesis of this complex disorder. Apoptotic cell death forms a second dominant feature of septic shock in patients and animal models. Anti-apoptotic strategies may protect animals from septic death. However, simultaneous occurrence of apoptosis and inflammation is necessary for septic death. At the cellular level, apoptosis plays a central role in the development of the lymphoid system and regulation of immune responses. Immune activation renders cells refractory to apoptosis while apoptosis of activated lymphocytes is an important immunoregulatory mechanism. Factors such as complement factor 5a, caspase-1 and mitogen-activated protein kinase, which participate in apoptosis as well as pro-inflammatory pathways, may be responsible for simultaneous activation of apoptosis and inflammation in sepsis. Further identification of other similar biochemical events capable of co-activating inflammation and apoptosis may provide new targets for therapy of this hitherto untreatable disease.
Rapid analysis of the Vβ repertoire of CD4 and CD8 T lymphocytes in whole blood
2003, Journal of Immunological Methods
Determination of the T cell receptor Vβ repertoire of human CD4 and CD8 populations is a useful immunological tool, particularly in the investigation of superantigen involvement in various disease states. We describe the optimisation of a rapid technique for the simultaneous evaluation of 24 Vβ families of the T cell receptor of CD4 and CD8 positive lymphocytes in whole blood by flow cytometry adapting a commercially available monoclonal antibody kit. The technique described is reliable and reproducible, and we describe its use as a potential diagnostic tool in patients with staphylococcal and streptococcal toxic shock syndromes.
Double mutant and formaldehyde inactivated TSST-1 as vaccine candidates for TSST-1-induced toxic shock syndrome
2002, Vaccine
Up to now there is no treatment for staphylococcal toxic shock syndrome, a disease mainly induced by toxic shock syndrome toxin-1(TSST-1). There is great demand in finding means to control the disease, one of them is the development of an effective and safe vaccine against TSST-1. In this study we constructed a series of vaccine candidates and investigated their biological activity, toxicity, and potential to invoke an immune response. TSST-1 was isolated from Stahylococcus aureus supernatants and recombinantly expressed as a N-terminal 6× histidine-tagged protein in Escherichia coli. In order to obtain molecules with minimal toxicity we constructed single mutants (G31R and H135A) and one double mutant (G31R/H135A) with both residues exchanged. We also detoxified native TSST-1 isolated from S. aureus, and recombinantly expressed TSST-1 by treatment with formaldehyde. Functional activity of native and recombinant TSST-1 and grade of inocuity of mutants and toxoids was determined by investigating mitogenity, T-cell activation, and cytokine release upon stimulation of human mononuclear cells with the vaccine candidates. All substances were tested in a rabbit immunization study. After primary immunization and three additional boosts all vaccinated animals developed antibody titers against TSST-1 and were protected against challenge with a lethal doses of superantigen potentiated with lipopolysaccharide.

View all citing articles on Scopus

: Address reprint requests to John B. Zabriskie, MD, Rockefeller University, 1230 York Ave, New York, New York 10021

View full text

STRUCTURE AND FUNCTION OF STREPTOCOCCAL AND STAPHYLOCOCCAL SUPERANTIGENS IN SEPTIC SHOCK

Section snippets

STRUCTURE AND FUNCTION

MITOGENIC ACTIVITY

CLINICAL MANIFESTATIONS

TWO-HIT HYPOTHESIS OF SEPTIC SHOCK

THERAPEUTIC MEASURES

J Lab Clin Med

J Immunol Methods

Cell Immunol

Adv Immunol

Immunol Lett

Clin Immunol Immunopathol

Biochem Biophys Res Commun

Diagn Microbiol Infect Dis

Biochem Biophys Res Commun

J Biol Chem

Biochem Biophys Res Commun

Mol Phylogenet Evol

Biochim Biophys Acta

Cell

Structural basis of superantigen action inferred from crystal structure of toxic-shock syndrome toxin-1

Nature

Lymphokine production induced by streptococcal pyrogenic exotoxin-A is selectively down-regulated by pooled human IgG

Eur J Immunol

Neutralization of streptococcal pyrogenic exotoxins and staphylococcal enterotoxins by antisera to synthetic peptides representing conserved amino acid motifs

Adv Exp Med Biol

The staphylococcal enterotoxins—An update

Superantigens and endotoxin synergize in the induction of lethal shock

Eur J Immunol

The nucleotide and partial amino acid sequence of toxic shock syndrome toxin-1

J Biol Chem

Cross-neutralization of staphylococcal and streptococcal pyrogenic toxins by monoclonal and polyclonal antibodies

Infect Immun

Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen

Nature

Differential RNA regulation by staphylococcal enterotoxins A and B in murine macrophages

J Leukoc Biol

Interaction of Staphylococcus aureus toxin superantigens with human T cells

Proc Natl Acad Sci U S A

Specificity and cross-reactivity of staphylococcal enterotoxin A monoclonal antibodies with enterotoxins B, C1, D, and E

Appl Environ Microbiol

T cell stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for major histocompatibility complex class II molecules on accessory or target cells

J Exp Med

A co-stimulatory role for CD28 in the activation of CD4+ T lymphocytes by staphylococcal enterotoxin B

Int Immunol

Nucleotide sequence of streptococcal exotoxin type C

Infect Immun

Mapping of multiple binding domains of the superantigen staphylococcal enterotoxin A for HLA

J Immunol

Dissociation of the stimulatory activities of staphylococcal enterotoxins for T cells and monocytes

J Exp Med

Mutation of the disulfide loop in staphylococcal enterotoxin A. Consequences for T cell recognition

J Immunol

Superantigens associated with staphylococcal and streptococcal toxic shock syndrome are potent inducers of tumor necrosis factor beta synthesis

J Infect Dis

Mutations affecting MHC class II binding of the superantigen streptococcal erythrogenic toxin A

Int Immunol

Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock–like syndrome

J Clin Microbiol