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Malak Kotb - One of the best experts on this subject based on the ideXlab platform.
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individual genetic variations directly effect polarization of cytokine responses to Superantigens associated with streptococcal sepsis implications for customized patient care
2011Co-Authors: Mohammed M Nooh, Malak Kotb, Suba Nookala, Rita KansalAbstract:Host immunogenetic variations strongly influence the severity of group A streptococcus sepsis by modulating responses to streptococcal Superantigens (Strep-SAgs). Although HLA-II-DR15/DQ6 alleles strongly protect against severe sepsis, HLA-II-DR14/DR7/DQ5 alleles significantly increase the risk for toxic shock syndrome. We found that, regardless of individual variations in TCR-Vβ repertoires, the presentation of Strep-SAgs by the protective HLA-II-DR15/DQ6 alleles significantly attenuated proliferative responses to Strep-SAgs, whereas their presentation by the high-risk alleles augmented it. Importantly, HLA-II variations differentially polarized cytokine responses to Strep-SAgs: the presentation of Strep-SAgs by HLA-II-DR15/DQ6 alleles elicited significantly higher ratios of anti-inflammatory cytokines (e.g., IL-10) to proinflammatory cytokines (e.g., IFN-γ) than did their presentation by the high-risk HLA-II alleles. Adding exogenous rIL-10 significantly attenuated responses to Strep-SAgs presented by the high-risk HLA-II alleles but did not completely block the response; instead, it reduced it to a level comparable to that seen when these Superantigens were presented by the protective HLA-II alleles. Furthermore, adding neutralizing anti-IL-10 Abs augmented Strep-SAg responses in the presence of protective HLA-II alleles to the same level as (but no higher than) that seen when the Superantigens were presented by the high-risk alleles. Our findings provide a molecular basis for the role of HLA-II allelic variations in modulating streptococcal sepsis outcomes and suggest the presence of an internal control mechanism that maintains superantigen responses within a defined range, which helps to eradicate the infection while attenuating pathological inflammatory responses that can inflict more harm than the infection itself.
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evidence for superantigen involvement in severe group a streptococcal tissue infections
2001Co-Authors: Anna Norrbyteglund, Malak Kotb, Jan Andersson, Allison Mcgeer, Pontus Thulin, Bing S Gan, Donald E LowAbstract:Host-pathogen interactions were studied in tissue biopsy samples from patients with severe invasive group A streptococcus (GAS) infections. Skin, subcutaneous tissue, and fascia biopsy samples were divided into clinical grade 1 (no evidence of inflammation [n=7]) or clinical grade 2 (inflamed tissue--erythema and edema including cellulitis, fasciitis, and necrotizing fasciitis [n=24]). In situ imaging demonstrated significantly higher bacterial load in biopsy samples of higher clinical grade (P<.05), and the bacterial load correlated with the in vivo expression of the superantigen streptococcal pyrogenic exotoxin F (P<.02). Increased expression of the interleukin-1 cytokines and significantly higher expression of tumor necrosis factor-beta, interferon-gamma, and the homing receptors CC chemokine receptor 5, CD44, and cutaneous lymphocyte-associated antigen (P<.002-.05) were observed in biopsy samples of higher clinical grade. Thus, the cytokine profile at the local site of infection mimics that of a typical superantigen cytokine response. The findings of this study demonstrate a critical role for Superantigens and Th1 cytokines in GAS tissue infections.
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varying titers of neutralizing antibodies to streptococcal Superantigens in different preparations of normal polyspecific immunoglobulin g implications for therapeutic efficacy
1998Co-Authors: Anna Norrbyteglund, Hesham E Basma, Jan Andersson, Allison Mcgeer, Donald E Low, Malak KotbAbstract:Inasmuch as normal intravenous polyspecific immunoglobulin G (IVIG) neutralizes the activity of a wide spectrum of Superantigens, it may be an efficient adjunctive therapy for diseases associated with superantigen-producing organisms, including severe group A streptococcal diseases. The neutralizing activity against purified Superantigens, streptococcal pyrogenic exotoxins (Spe), and a mixture of Superantigens present in culture supernatant of clinical group A streptococcal isolates was determined for five IVIG preparations. A significant variation among different IVIG preparations (Po .05) and different lots of the same IVIG brand (Po .044) was found. Neutralization of SpeA activity was significantly lower than that of other streptococcal Superantigens (P o .05); however, there was no correlation between SpeA binding and SpeA neutralizing activity in different IVIGs. Plasma samples obtained from patients after IVIG infusion varied in their titers of neutralizing antibodies to culture supernatants prepared from their respective isolates, and this variation paralleled differences in the neutralizing titer of the IVIG lot administered to each patient studied. The study suggests that complete neutralizing activity may be achieved by optimizing the type and/or dose of IVIG used in treatment. Streptococcal toxic shock syndrome and necrotizing fasciitis scores the need for a therapeutic agent that has a broad specificity against a wide variety of group A streptococcal superantiare the two most severe manifestations caused by invasive group A streptococcus, and despite appropriate antibiotic ther- gens.
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plasma from patients with severe invasive group a streptococcal infections treated with normal polyspecific igg inhibits streptococcal superantigen induced t cell proliferation and cytokine production
1996Co-Authors: Anna Norrbyteglund, Jan Andersson, Allison Mcgeer, Donald E Low, Ulf Andersson, Rupert Kaul, Duane W Newton, Malak KotbAbstract:Previous studies have suggested a central role for superantigen-induced immune responses in the pathogenesis of streptococcal toxic shock syndrome. The production of streptococcal Superantigens by clinical group A streptococcal (GAS) isolates was studied, and the ability of plasma collected from patients with severe invasive GAS infections to neutralize the proliferative- and cytokine-inducing activities of these Superantigens was investigated. Overnight culture supernatants from all GAS isolates obtained from patients with invasive disease were found to contain superantigenic activity, as evident from their ability to drive potent T cell proliferation, induce high production of cytokines, and stimulate T cells in a V beta-specific manner. Twelve patients with severe invasive GAS infections, including 11 streptococcal toxic shock syndrome cases and one necrotizing fasciitis without shock, were treated with i.v. infusions of normal polyspecific Ig (IVIG). Plasma samples collected from each patient before and after IVIG administration were analyzed for their ability to neutralize the activity of streptococcal Superantigens produced by the GAS isolate that caused their disease. In all IVIG-treated patients, the capacity to neutralize the superantigenic activity, produced by their respective GAS isolate or by purified streptococcal pyrogenic exotoxins, increased in plasma following IVIG administration. Of particular clinical relevance, post-IVIG plasma from each patient completely blocked cytokine production elicited by their respective GAS culture supernatants or by purified streptococcal pyrogenic exotoxins. This study shows that IVIG treatment confers in vivo inhibitory activity against a large array of streptococcal Superantigens and suggests that IVIG may be useful in the treatment of severe invasive streptococcal infections.
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bacterial pyrogenic exotoxins as Superantigens
1995Co-Authors: Malak KotbAbstract:The recent discovery of the mode of interaction between a group of microbial proteins known as Superantigens and the immune system has opened a wide area of investigation into the possible role of these molecules in human diseases. Superantigens produced by certain viruses and bacteria, including Mycoplasma species, are either secreted or membrane-bound proteins. A unique feature of these proteins is that they can interact simultaneously with distinct receptors on different types of cells, resulting in enhanced cell-cell interaction and triggering a series of biochemical reactions that can lead to excessive cell proliferation and the release of inflammatory cytokines. However, although Superantigens share many features, they can have very different biological effects that are potentiated by host genetic and environmental factors. This review focuses on a group of secreted pyrogenic toxins that belong to the superantigen family and highlights some of their structural-functional features and their roles in diseases such as toxic shock and autoimmunity. Deciphering the biological activities of the various Superantigens and understanding their role in the pathogenesis of microbial infections and their sequelae will enable us to devise means by which we can intervene with their activity and/or manipulate them to our advantage.
Donald Y M Leung - One of the best experts on this subject based on the ideXlab platform.
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Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines.
2019Co-Authors: Patrick M. Schlievert, Amanda J. Brosnahan, Aloysius J Klingelhutz, Michael P. Cahill, Bruce S. Hostager, Francoise A. Gourronc, Gail A. Bishop, Donald Y M LeungAbstract:ABSTRACT Mucosal and skin tissues form barriers to infection by most bacterial pathogens. Staphylococcus aureus causes diseases across these barriers in part dependent on the proinflammatory properties of Superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the Superantigens toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins (SEs) B and C stimulated chemokine production from human vaginal epithelial cells (HVECs) through human CD40. This response was enhanced by addition of antibodies against CD40 through an unknown mechanism. TSST-1 was better able to stimulate chemokine (IL-8 and MIP-3α) production by HVECs than SEB and SEC, suggesting this is the reason for TSST-1’s exclusive association with menstrual TSS. A mutant of TSST-1, K121A, caused TSS in a rabbit model when administered vaginally but not intravenously, emphasizing the importance of the local vaginal environment. Collectively, our data suggested that Superantigens facilitate infections by disruption of mucosal barriers through their binding to CD40, with subsequent expression of chemokines. The chemokines facilitate TSS and possibly other epithelial conditions after attraction of the adaptive immune system to the local environment. IMPORTANCE Menstrual toxic shock syndrome (TSS) is a serious infectious disease associated with vaginal colonization by Staphylococcus aureus producing the exotoxin TSS toxin 1 (TSST-1). We show that menstrual TSS occurs after TSST-1 interaction with an immune costimulatory molecule called CD40 on the surface of vaginal epithelial cells. Other related toxins, where the entire family is called the superantigen family, bind to CD40, but not with a high-enough apparent affinity to cause TSS; thus, TSST-1 is the only exotoxin superantigen associated. Once the epithelial cells become activated by TSST-1, they produce soluble molecules referred to as chemokines, which in turn facilitate TSST-1 activation of T lymphocytes and macrophages to cause the symptoms of TSS. Identification of small-molecule inhibitors of the interaction of TSST-1 with CD40 may be useful so that they may serve as additives to medical devices, such as tampons and menstrual cups, to reduce the incidence of menstrual TSS.
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Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines
2019Co-Authors: Patrick M. Schlievert, Amanda J. Brosnahan, Aloysius J Klingelhutz, Michael P. Cahill, Bruce S. Hostager, Francoise A. Gourronc, Gail A. Bishop, Donald Y M LeungAbstract:Menstrual toxic shock syndrome (TSS) is a serious infectious disease associated with vaginal colonization by Staphylococcus aureus producing the exotoxin TSS toxin 1 (TSST-1). We show that menstrual TSS occurs after TSST-1 interaction with an immune costimulatory molecule called CD40 on the surface of vaginal epithelial cells. Other related toxins, where the entire family is called the superantigen family, bind to CD40, but not with a high-enough apparent affinity to cause TSS; thus, TSST-1 is the only exotoxin superantigen associated. Once the epithelial cells become activated by TSST-1, they produce soluble molecules referred to as chemokines, which in turn facilitate TSST-1 activation of T lymphocytes and macrophages to cause the symptoms of TSS. Identification of small-molecule inhibitors of the interaction of TSST-1 with CD40 may be useful so that they may serve as additives to medical devices, such as tampons and menstrual cups, to reduce the incidence of menstrual TSS.Mucosal and skin tissues form barriers to infection by most bacterial pathogens. Staphylococcus aureus causes diseases across these barriers in part dependent on the proinflammatory properties of Superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the Superantigens toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins (SEs) B and C stimulated chemokine production from human vaginal epithelial cells (HVECs) through human CD40. This response was enhanced by addition of antibodies against CD40 through an unknown mechanism. TSST-1 was better able to stimulate chemokine (IL-8 and MIP-3α) production by HVECs than SEB and SEC, suggesting this is the reason for TSST-1’s exclusive association with menstrual TSS. A mutant of TSST-1, K121A, caused TSS in a rabbit model when administered vaginally but not intravenously, emphasizing the importance of the local vaginal environment. Collectively, our data suggested that Superantigens facilitate infections by disruption of mucosal barriers through their binding to CD40, with subsequent expression of chemokines. The chemokines facilitate TSS and possibly other epithelial conditions after attraction of the adaptive immune system to the local environment
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superantigen profile of staphylococcus aureus isolates from patients with steroid resistant atopic dermatitis
2008Co-Authors: Patrick M. Schlievert, Kristi L. Strandberg, Laura C Case, Bea B Abrams, Donald Y M LeungAbstract:Staphylococcus aureus is a commensal organism that colonizes up to 50% of humans [1, 2]. The organism most often colonizes the anterior nares and, from there, may colonize other body surfaces, including other mucous membranes and damaged skin. S. aureus causes a wide variety of human illnesses, including scalded skin syndrome, toxic shock syndrome (TSS), and necrotizing pneumonia [3-9]. The ability of S. aureus to cause human disease depends on the production of cell-surface adhesins, antiphagocytic factors, and secreted exotoxins, whose functions appear to be both securing nutrients for the microbes and delaying function of the immune system [10-12]. Among the secreted factors is a large family of superantigen exotoxins [8]. Staphylococcal Superantigens include staphylococcal enterotoxins, classically the common causes of food poisoning and nonmenstrual TSS, and TSS toxin 1 (TSST-1), the cause of both menstrual and nonmenstrual TSS [8]. Staphylococcal enterotoxin serotypes A–E (SEA–SEE) and SEG–SEQ have been well described in the literature. SEA–SEE and SEI are capable of causing vomiting and diarrhea when administered to monkeys and, thus, are correctly referred to as staphylococcal enterotoxins [13]. The remaining staphylococcal enterotoxins either lack emetic activity (SEG, SEK, SEL, and SEQ) or have not been tested for emetic activity. According to the suggestions of a recent nomenclature committee, these Superantigens are more correctly designated as staphylococcal enterotoxin–like (SEl) (SEl-G, -H, -J, -K, -L, -M, -N, -O, -P, and -Q) [14]. Superantigens are defined by their ability to stimulate cytokine release from both T cells and macrophages [15]. The proteins bind to relatively invariant regions of major histocompatibility complex II molecules on antigen-presenting cells, and they cross-bridge with certain variable regions of the beta-chains of T cell receptors (Vb-TCR) [16]. Each superantigen has a relatively unique subset of Vb-TCR interactions. For example, TSST-1 stimulates only T cells bearing Vb2-TCRs, but these account for only ∼10% of the total repertoire of T cells in humans [16]. However, during acute TSS, T cells bearing Vb2-TCRs may proliferate in a skewed manner, such that the activated T cells account for 60% of the patients’ T cells [17]. The massive cytokine release by both T cells and macrophages accounts for the most-severe manifestations of superantigen-mediated illnesses [8, 15, 16]. Atopic dermatitis is a T cell–mediated skin disease that can significantly compromise quality of life, because patients experience sleep disturbances, social embarrassment, and emotional distress. S. aureus infection contributes to the worsening of skin inflammation in atopic dermatitis [18-20]. These organisms have been shown to produce Superantigens, including SEA, SEB, SEC, and TSST-1. However, the full spectrum of Superantigens produced by S. aureus isolates that infect patients with atopic dermatitis has not been examined previously. Furthermore, Superantigens have been demonstrated to induce corticosteroid resistance of T cells in vitro [21]. This could contribute to difficulty in management of atopic dermatitis, because topical corticosteroids are the most common medication used for treatment of atopic dermatitis. The present study, therefore, was undertaken to characterize S. aureus isolates from patients with steroid-resistant atopic dermatitis with regard to their ability to produce Superantigens.
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role of bacterial Superantigens in atopic dermatitis implications for future therapeutic strategies
2006Co-Authors: Ivan D Cardona, Donald Y M Leung, Sanghyun ChoAbstract:The role of staphylococcal Superantigens in the pathophysiology of atopic dermatitis (AD) has been the focus of intense interest during the past decade. Although the increased prevalence of Staphylococcus aureus and its bacterial toxins in AD skin is well established, exploitation of the known mechanisms of Superantigens in this disease for the development of novel therapies remains an active area of research. With the emergence of multi-drug resistant S. aureus, the need for a better understanding of the pathophysiology of bacterial Superantigens in AD has become increasingly important. This review examines the mechanisms of S. aureus colonization and infection, of which the most important are defective skin barrier function, increased S. aureus adherence, and the decreased innate immune responses found in AD skin. The contribution of Superantigens to the pathophysiology of AD is then discussed. Important immunologic mechanisms in this context include the role of Superantigens in promoting T helper-2 skin inflammation, IgE production, T-regulatory cell subversion, expansion and migration of skin-homing T cells, and IgE anti-superantigen production. Lastly, these findings are discussed with reference to current therapeutic approaches, of which the most important include anti-inflammatory and antimicrobial medications, and future strategies, which are expected to consist of immune-modulators and synthetic antibacterials.
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superantigen induced corticosteroid resistance of human t cells occurs through activation of the mitogen activated protein kinase kinase extracellular signal regulated kinase mek erk pathway
2004Co-Authors: Elena Goleva, Clifton F Hall, Donald Y M LeungAbstract:Background Microbial Superantigens induce human T-cell resistance to corticosteroids. Objective Understanding the molecular pathways resulting in corticosteroid-resistant T cells is important because this condition can complicate the treatment of inflammation. Methods The response of human PBMCs to steroids was assessed by using proliferation assays after stimulation with Superantigens or anti-CD3 in the presence of various kinase inhibitors. Glucocorticoid receptor α (GCRα) localization was defined on the basis of intracellular staining. Protein phosphorylation was measured by means of Western blotting. Results In the current study we found that PBMCs stimulated with superantigen, but not anti-CD3, induced corticosteroid-resistant T cells. However, the purified T cells stimulated either with staphylococcal enterotoxin B (SEB) or anti-CD3 are susceptible to corticosteroid inhibition. These results imply that signals on antigen-presenting cells might act in concert with the T-cell receptor to cause steroid resistance. Blockade of CD40–CD40 ligand interaction had no effect on superantigen-induced corticosteroid resistance. However, CD28 costimulation with T-cell receptor activation induced corticosteroid resistance of human T cells in a dose-dependent manner. Superantigen stimulation, compared with anti-CD3 stimulation, was found to induce a more rapid and sustained phosphorylation of mitogen-activated extracellular signal-regulated kinase (ERK). Treatment with PD98059 and UO126 (specific mitogen-activated protein kinase kinase [MEK]/ERK inhibitors), but not a p38 inhibitor or a c-Jun N-terminal kinase inhibitor, restored the response to steroids, as indicated by proliferation assays. Furthermore, purified ERK1 and ERK2 were able to phosphorylate recombinant human GCRα directly in an in vitro kinase assay. Of note, superantigen-induced corticosteroid resistance was associated with abrogation of GCRα nuclear translocation. This effect could be reversed by treatment with MEK/ERK pathway inhibitors. Conclusions These data are compatible with the hypothesis that superantigen-induced corticosteroid resistance involves the Raf-MEK-ERK1/ERK2 pathway of T-cell receptor signaling, which leads to GCRα phosphorylation and inhibition of dexamethasone-induced GCRα nuclear translocation.
Patrick M. Schlievert - One of the best experts on this subject based on the ideXlab platform.
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Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines.
2019Co-Authors: Patrick M. Schlievert, Amanda J. Brosnahan, Aloysius J Klingelhutz, Michael P. Cahill, Bruce S. Hostager, Francoise A. Gourronc, Gail A. Bishop, Donald Y M LeungAbstract:ABSTRACT Mucosal and skin tissues form barriers to infection by most bacterial pathogens. Staphylococcus aureus causes diseases across these barriers in part dependent on the proinflammatory properties of Superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the Superantigens toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins (SEs) B and C stimulated chemokine production from human vaginal epithelial cells (HVECs) through human CD40. This response was enhanced by addition of antibodies against CD40 through an unknown mechanism. TSST-1 was better able to stimulate chemokine (IL-8 and MIP-3α) production by HVECs than SEB and SEC, suggesting this is the reason for TSST-1’s exclusive association with menstrual TSS. A mutant of TSST-1, K121A, caused TSS in a rabbit model when administered vaginally but not intravenously, emphasizing the importance of the local vaginal environment. Collectively, our data suggested that Superantigens facilitate infections by disruption of mucosal barriers through their binding to CD40, with subsequent expression of chemokines. The chemokines facilitate TSS and possibly other epithelial conditions after attraction of the adaptive immune system to the local environment. IMPORTANCE Menstrual toxic shock syndrome (TSS) is a serious infectious disease associated with vaginal colonization by Staphylococcus aureus producing the exotoxin TSS toxin 1 (TSST-1). We show that menstrual TSS occurs after TSST-1 interaction with an immune costimulatory molecule called CD40 on the surface of vaginal epithelial cells. Other related toxins, where the entire family is called the superantigen family, bind to CD40, but not with a high-enough apparent affinity to cause TSS; thus, TSST-1 is the only exotoxin superantigen associated. Once the epithelial cells become activated by TSST-1, they produce soluble molecules referred to as chemokines, which in turn facilitate TSST-1 activation of T lymphocytes and macrophages to cause the symptoms of TSS. Identification of small-molecule inhibitors of the interaction of TSST-1 with CD40 may be useful so that they may serve as additives to medical devices, such as tampons and menstrual cups, to reduce the incidence of menstrual TSS.
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Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines
2019Co-Authors: Patrick M. Schlievert, Amanda J. Brosnahan, Aloysius J Klingelhutz, Michael P. Cahill, Bruce S. Hostager, Francoise A. Gourronc, Gail A. Bishop, Donald Y M LeungAbstract:Menstrual toxic shock syndrome (TSS) is a serious infectious disease associated with vaginal colonization by Staphylococcus aureus producing the exotoxin TSS toxin 1 (TSST-1). We show that menstrual TSS occurs after TSST-1 interaction with an immune costimulatory molecule called CD40 on the surface of vaginal epithelial cells. Other related toxins, where the entire family is called the superantigen family, bind to CD40, but not with a high-enough apparent affinity to cause TSS; thus, TSST-1 is the only exotoxin superantigen associated. Once the epithelial cells become activated by TSST-1, they produce soluble molecules referred to as chemokines, which in turn facilitate TSST-1 activation of T lymphocytes and macrophages to cause the symptoms of TSS. Identification of small-molecule inhibitors of the interaction of TSST-1 with CD40 may be useful so that they may serve as additives to medical devices, such as tampons and menstrual cups, to reduce the incidence of menstrual TSS.Mucosal and skin tissues form barriers to infection by most bacterial pathogens. Staphylococcus aureus causes diseases across these barriers in part dependent on the proinflammatory properties of Superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the Superantigens toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins (SEs) B and C stimulated chemokine production from human vaginal epithelial cells (HVECs) through human CD40. This response was enhanced by addition of antibodies against CD40 through an unknown mechanism. TSST-1 was better able to stimulate chemokine (IL-8 and MIP-3α) production by HVECs than SEB and SEC, suggesting this is the reason for TSST-1’s exclusive association with menstrual TSS. A mutant of TSST-1, K121A, caused TSS in a rabbit model when administered vaginally but not intravenously, emphasizing the importance of the local vaginal environment. Collectively, our data suggested that Superantigens facilitate infections by disruption of mucosal barriers through their binding to CD40, with subsequent expression of chemokines. The chemokines facilitate TSS and possibly other epithelial conditions after attraction of the adaptive immune system to the local environment
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chronic superantigen exposure induces systemic inflammation elevated bloodstream endotoxin and abnormal glucose tolerance in rabbits possible role in diabetes
2015Co-Authors: Christopher S Stach, Katarina Kulhankova, Wilmara Salgadopabon, Aloysius J Klingelhutz, Patrick M. SchlievertAbstract:ABSTRACT Excessive weight and obesity are associated with the development of diabetes mellitus type 2 (DMII) in humans. They also pose high risks of Staphylococcus aureus colonization and overt infections. S. aureus causes a wide range of severe illnesses in both healthy and immunocompromised individuals. Among S. aureus virulence factors, Superantigens are essential for pathogenicity. In this study, we show that rabbits that are chronically exposed to S. aureus superantigen toxic shock syndrome toxin-1 (TSST-1) experience impaired glucose tolerance, systemic inflammation, and elevated endotoxin levels in the bloodstream, all of which are common findings in DMII. Additionally, such DMII-associated findings are also seen through effects of TSST-1 on isolated adipocytes. Collectively, our findings suggest that chronic exposure to S. aureus Superantigens facilitates the development of DMII, which may lead to therapeutic targeting of S. aureus and its Superantigens. IMPORTANCE Obesity has a strong correlation with type 2 diabetes, in which fatty tissue, containing adipocytes, contributes to the development of the illness through altered metabolism and chronic inflammation. The human microbiome changes in persons with obesity and type 2 diabetes, including increases in Staphylococcus aureus colonization and overt infections. While the microbiome is essential for human wellness, there is little understanding of the role of microbes in obesity or the development of diabetes. Here, we demonstrate that the S. aureus superantigen toxic shock syndrome toxin-1 (TSST-1), an essential exotoxin in pathogenesis, induces inflammation, lipolysis, and insulin resistance in adipocytes both in vitro and in vivo . Chronic stimulation of rabbits with TSST-1 results in impaired systemic glucose tolerance, the hallmark finding in type 2 diabetes in humans, suggesting a role of S. aureus and its Superantigens in the progression to type 2 diabetes.
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Staphylococcal Superantigens Cause Lethal Pulmonary Disease in Rabbits
2010Co-Authors: Kristi L. Strandberg, Jessica H. Rotschafer, Sara M. Vetter, Rebecca A. Buonpane, David M. Kranz, Patrick M. SchlievertAbstract:Background The Centers for Disease Control and Prevention (CDC) and others reported that methicillin-resistant S. aureus (MRSA) are significant causes of serious human infections, including pulmonary illnesses. We investigated the role played by Superantigens in lung-associated lethal illness in rabbits. Methods A rabbit model was established to investigate the potential role played by Superantigens, staphylococcal enterotoxin B (SEB), staphylococcal enterotoxin C (SEC), and toxic shock syndrome toxin-1 (TSST-1). Rabbits received intrabronchial community-associated (CA) MRSA strains USA200 (TSST-1(+)), MW2 (SEC(+)), c99-529 (SEB(+)), or purified Superantigens. Some rabbits were preimmunized against Superantigens or treated with soluble high-affinity T cell receptors (Vβ-TCR) to neutralize SEB and then challenged intrabronchially with CA-MRSA or Superantigens. Results Rabbits challenged with CA-MRSA or Superantigens developed fatal, pulmonary illnesses. Animals preimmunized against purified Superantigens, or treated passively with Vβ-TCRs and then challenged with CA-MRSA or Superantigens, survived. Lung histological analysis indicated that nonimmune animals developed lesions consistent with necrotizing pneumonia after challenge with CA-MRSA or purified Superantigens. Superantigen-immune animals or animals treated with soluble Vβ-TCRs did not develop pulmonary lesions. Conclusions Superantigens contribute to lethal pulmonary illnesses due to CA-MRSA; preexisting immunity to Superantigens prevents lethality. Administration of high-affinity Vβ-TCR with specificity for SEB to nonimmune animals protects from lethal pulmonary illness resulting from SEB(+) CA-MRSA and SEB.
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Cytolysins augment superantigen penetration of stratified mucosa
2009Co-Authors: Amanda J. Brosnahan, Mary J. Mantz, Christopher A. Squier, Marnie L. Peterson, Patrick M. SchlievertAbstract:Staphylococcus aureus and Streptococcus pyogenes colonize mucosal surfaces of the human body to cause disease. A group of virulence factors known as Superantigens are produced by both of these organisms that allows them to cause serious diseases from the vaginal (staphylococci) or oral mucosa (streptococci) of the body. Superantigens interact with T cells and APCs to cause massive cytokine release to mediate the symptoms collectively known as toxic shock syndrome. In this study we demonstrate that another group of virulence factors, cytolysins, aid in the penetration of Superantigens across vaginal mucosa as a representative nonkeratinized stratified squamous epithelial surface. The staphylococcal cytolysin α-toxin and the streptococcal cytolysin streptolysin O enhanced penetration of toxic shock syndrome toxin-1 and streptococcal pyrogenic exotoxin A, respectively, across porcine vaginal mucosa in an ex vivo model of superantigen penetration. Upon histological examination, both cytolysins caused damage to the uppermost layers of the vaginal tissue. In vitro evidence using immortalized human vaginal epithelial cells demonstrated that although both Superantigens were proinflammatory, only the staphylococcal cytolysin α-toxin induced a strong immune response from the cells. Streptolysin O damaged and killed the cells quickly, allowing only a small release of IL-1β. Two separate models of superantigen penetration are proposed: staphylococcal α-toxin induces a strong proinflammatory response from epithelial cells to disrupt the mucosa enough to allow for enhanced penetration of toxic shock syndrome toxin-1, whereas streptolysin O directly damages the mucosa to allow for penetration of streptococcal pyrogenic exotoxin A and possibly viable streptococci.
Anna Norrbyteglund - One of the best experts on this subject based on the ideXlab platform.
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differences in potency of intravenous polyspecific immunoglobulin g against streptococcal and staphylococcal Superantigens implications for therapy of toxic shock syndrome
2004Co-Authors: Jessica Darenberg, Bo Soderquist, Birgitta Henriques Normark, Anna NorrbyteglundAbstract:Administration of intravenous polyspecific immunoglobulin G (IVIG) has been proposed as adjunctive therapy for toxic shock syndrome caused by Streptococcus pyogenes or Staphylococcus aureus. We investigated whether superantigen-containing culture supernatants prepared from streptococcal isolates (n=21) and staphylococcal isolates (n=20) from cases of severe sepsis were inhibited to an equal extent by IVIG in proliferation experiments that used human peripheral blood mononuclear cells. All 3 IVIG preparations tested were highly efficient in neutralizing the Superantigens, and most supernatants were completely inhibited at concentrations ranging from 0.05 to 2.5 mg IVIG/mL. An important finding was that culture supernatants from S. pyogenes isolates were consistently inhibited to a greater extent than those of S. aureus isolates (P<.01). The findings demonstrate that staphylococcal Superantigens are not inhibited as efficiently as streptococcal Superantigens by IVIG, and, hence, a higher dose of IVIG may be required for therapy of staphylococcal toxic shock syndrome in order to achieve protective titers and clinical efficacy.
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evidence for superantigen involvement in severe group a streptococcal tissue infections
2001Co-Authors: Anna Norrbyteglund, Malak Kotb, Jan Andersson, Allison Mcgeer, Pontus Thulin, Bing S Gan, Donald E LowAbstract:Host-pathogen interactions were studied in tissue biopsy samples from patients with severe invasive group A streptococcus (GAS) infections. Skin, subcutaneous tissue, and fascia biopsy samples were divided into clinical grade 1 (no evidence of inflammation [n=7]) or clinical grade 2 (inflamed tissue--erythema and edema including cellulitis, fasciitis, and necrotizing fasciitis [n=24]). In situ imaging demonstrated significantly higher bacterial load in biopsy samples of higher clinical grade (P<.05), and the bacterial load correlated with the in vivo expression of the superantigen streptococcal pyrogenic exotoxin F (P<.02). Increased expression of the interleukin-1 cytokines and significantly higher expression of tumor necrosis factor-beta, interferon-gamma, and the homing receptors CC chemokine receptor 5, CD44, and cutaneous lymphocyte-associated antigen (P<.002-.05) were observed in biopsy samples of higher clinical grade. Thus, the cytokine profile at the local site of infection mimics that of a typical superantigen cytokine response. The findings of this study demonstrate a critical role for Superantigens and Th1 cytokines in GAS tissue infections.
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varying titers of neutralizing antibodies to streptococcal Superantigens in different preparations of normal polyspecific immunoglobulin g implications for therapeutic efficacy
1998Co-Authors: Anna Norrbyteglund, Hesham E Basma, Jan Andersson, Allison Mcgeer, Donald E Low, Malak KotbAbstract:Inasmuch as normal intravenous polyspecific immunoglobulin G (IVIG) neutralizes the activity of a wide spectrum of Superantigens, it may be an efficient adjunctive therapy for diseases associated with superantigen-producing organisms, including severe group A streptococcal diseases. The neutralizing activity against purified Superantigens, streptococcal pyrogenic exotoxins (Spe), and a mixture of Superantigens present in culture supernatant of clinical group A streptococcal isolates was determined for five IVIG preparations. A significant variation among different IVIG preparations (Po .05) and different lots of the same IVIG brand (Po .044) was found. Neutralization of SpeA activity was significantly lower than that of other streptococcal Superantigens (P o .05); however, there was no correlation between SpeA binding and SpeA neutralizing activity in different IVIGs. Plasma samples obtained from patients after IVIG infusion varied in their titers of neutralizing antibodies to culture supernatants prepared from their respective isolates, and this variation paralleled differences in the neutralizing titer of the IVIG lot administered to each patient studied. The study suggests that complete neutralizing activity may be achieved by optimizing the type and/or dose of IVIG used in treatment. Streptococcal toxic shock syndrome and necrotizing fasciitis scores the need for a therapeutic agent that has a broad specificity against a wide variety of group A streptococcal superantiare the two most severe manifestations caused by invasive group A streptococcus, and despite appropriate antibiotic ther- gens.
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plasma from patients with severe invasive group a streptococcal infections treated with normal polyspecific igg inhibits streptococcal superantigen induced t cell proliferation and cytokine production
1996Co-Authors: Anna Norrbyteglund, Jan Andersson, Allison Mcgeer, Donald E Low, Ulf Andersson, Rupert Kaul, Duane W Newton, Malak KotbAbstract:Previous studies have suggested a central role for superantigen-induced immune responses in the pathogenesis of streptococcal toxic shock syndrome. The production of streptococcal Superantigens by clinical group A streptococcal (GAS) isolates was studied, and the ability of plasma collected from patients with severe invasive GAS infections to neutralize the proliferative- and cytokine-inducing activities of these Superantigens was investigated. Overnight culture supernatants from all GAS isolates obtained from patients with invasive disease were found to contain superantigenic activity, as evident from their ability to drive potent T cell proliferation, induce high production of cytokines, and stimulate T cells in a V beta-specific manner. Twelve patients with severe invasive GAS infections, including 11 streptococcal toxic shock syndrome cases and one necrotizing fasciitis without shock, were treated with i.v. infusions of normal polyspecific Ig (IVIG). Plasma samples collected from each patient before and after IVIG administration were analyzed for their ability to neutralize the activity of streptococcal Superantigens produced by the GAS isolate that caused their disease. In all IVIG-treated patients, the capacity to neutralize the superantigenic activity, produced by their respective GAS isolate or by purified streptococcal pyrogenic exotoxins, increased in plasma following IVIG administration. Of particular clinical relevance, post-IVIG plasma from each patient completely blocked cytokine production elicited by their respective GAS culture supernatants or by purified streptococcal pyrogenic exotoxins. This study shows that IVIG treatment confers in vivo inhibitory activity against a large array of streptococcal Superantigens and suggests that IVIG may be useful in the treatment of severe invasive streptococcal infections.
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evidence for superantigen involvement in severe group a streptococcal tissue infections
2001Co-Authors: Anna Norrbyteglund, Malak Kotb, Jan Andersson, Allison Mcgeer, Pontus Thulin, Bing S Gan, Donald E LowAbstract:Host-pathogen interactions were studied in tissue biopsy samples from patients with severe invasive group A streptococcus (GAS) infections. Skin, subcutaneous tissue, and fascia biopsy samples were divided into clinical grade 1 (no evidence of inflammation [n=7]) or clinical grade 2 (inflamed tissue--erythema and edema including cellulitis, fasciitis, and necrotizing fasciitis [n=24]). In situ imaging demonstrated significantly higher bacterial load in biopsy samples of higher clinical grade (P<.05), and the bacterial load correlated with the in vivo expression of the superantigen streptococcal pyrogenic exotoxin F (P<.02). Increased expression of the interleukin-1 cytokines and significantly higher expression of tumor necrosis factor-beta, interferon-gamma, and the homing receptors CC chemokine receptor 5, CD44, and cutaneous lymphocyte-associated antigen (P<.002-.05) were observed in biopsy samples of higher clinical grade. Thus, the cytokine profile at the local site of infection mimics that of a typical superantigen cytokine response. The findings of this study demonstrate a critical role for Superantigens and Th1 cytokines in GAS tissue infections.
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varying titers of neutralizing antibodies to streptococcal Superantigens in different preparations of normal polyspecific immunoglobulin g implications for therapeutic efficacy
1998Co-Authors: Anna Norrbyteglund, Hesham E Basma, Jan Andersson, Allison Mcgeer, Donald E Low, Malak KotbAbstract:Inasmuch as normal intravenous polyspecific immunoglobulin G (IVIG) neutralizes the activity of a wide spectrum of Superantigens, it may be an efficient adjunctive therapy for diseases associated with superantigen-producing organisms, including severe group A streptococcal diseases. The neutralizing activity against purified Superantigens, streptococcal pyrogenic exotoxins (Spe), and a mixture of Superantigens present in culture supernatant of clinical group A streptococcal isolates was determined for five IVIG preparations. A significant variation among different IVIG preparations (Po .05) and different lots of the same IVIG brand (Po .044) was found. Neutralization of SpeA activity was significantly lower than that of other streptococcal Superantigens (P o .05); however, there was no correlation between SpeA binding and SpeA neutralizing activity in different IVIGs. Plasma samples obtained from patients after IVIG infusion varied in their titers of neutralizing antibodies to culture supernatants prepared from their respective isolates, and this variation paralleled differences in the neutralizing titer of the IVIG lot administered to each patient studied. The study suggests that complete neutralizing activity may be achieved by optimizing the type and/or dose of IVIG used in treatment. Streptococcal toxic shock syndrome and necrotizing fasciitis scores the need for a therapeutic agent that has a broad specificity against a wide variety of group A streptococcal superantiare the two most severe manifestations caused by invasive group A streptococcus, and despite appropriate antibiotic ther- gens.
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plasma from patients with severe invasive group a streptococcal infections treated with normal polyspecific igg inhibits streptococcal superantigen induced t cell proliferation and cytokine production
1996Co-Authors: Anna Norrbyteglund, Jan Andersson, Allison Mcgeer, Donald E Low, Ulf Andersson, Rupert Kaul, Duane W Newton, Malak KotbAbstract:Previous studies have suggested a central role for superantigen-induced immune responses in the pathogenesis of streptococcal toxic shock syndrome. The production of streptococcal Superantigens by clinical group A streptococcal (GAS) isolates was studied, and the ability of plasma collected from patients with severe invasive GAS infections to neutralize the proliferative- and cytokine-inducing activities of these Superantigens was investigated. Overnight culture supernatants from all GAS isolates obtained from patients with invasive disease were found to contain superantigenic activity, as evident from their ability to drive potent T cell proliferation, induce high production of cytokines, and stimulate T cells in a V beta-specific manner. Twelve patients with severe invasive GAS infections, including 11 streptococcal toxic shock syndrome cases and one necrotizing fasciitis without shock, were treated with i.v. infusions of normal polyspecific Ig (IVIG). Plasma samples collected from each patient before and after IVIG administration were analyzed for their ability to neutralize the activity of streptococcal Superantigens produced by the GAS isolate that caused their disease. In all IVIG-treated patients, the capacity to neutralize the superantigenic activity, produced by their respective GAS isolate or by purified streptococcal pyrogenic exotoxins, increased in plasma following IVIG administration. Of particular clinical relevance, post-IVIG plasma from each patient completely blocked cytokine production elicited by their respective GAS culture supernatants or by purified streptococcal pyrogenic exotoxins. This study shows that IVIG treatment confers in vivo inhibitory activity against a large array of streptococcal Superantigens and suggests that IVIG may be useful in the treatment of severe invasive streptococcal infections.
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selective depletion of vβ bearing t cells in patients with severe invasive group a streptococcal infections and streptococcal toxic shock syndrome
1995Co-Authors: Rika Watanabeohnishi, Patrick M. Schlievert, Allison Mcgeer, Donald E Low, Duane W Newton, Dennis L Stevens, Benjamin Schwartz, Barry N Kreiswirth, Malak KotbAbstract:The V beta repertoire of T cells of patients with gram-positive group A streptococcal (GAS) and non-GAS infections was analyzed to seek evidence for the role of Superantigens in streptococcal toxic shock syndrome. No evidence of V beta overexpression but a consistent pattern of depletion of V beta 1, V beta 5.1, and V beta 12 was observed in patients with severe GAS infections. This pattern of V beta depletion was not observed in patients with nonsevere GAS infections or with severe non-GAS gram-positive infections. T cells from patients with severe GAS infections showed evidence of apoptosis; no apoptosis was found when there was no evidence of V beta depletion. There was no correlation with streptococcal M or T serotype or known spe genes. The depletion of specific V beta-bearing T cells in patients with severe GAS infections supports the role of a superantigen in these infections. The in vivo pattern of V beta specificity implicates a novel superantigen(s) in this disease.