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Special Issue "Enterotoxins: Microbial Proteins and Host Cell Dysregulation"

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (31 January 2015)

Special Issue Editor

Guest Editor
Dr. Teresa Krakauer

Department of Immunology, Integrated Toxicology Division, United States Army Medical Research, Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA
Phone: +1 301 619 4733
Fax: +1 301 619 2348

Special Issue Information

Dear Colleagues,

Enterotoxins encompass a diverse group of microbial toxins affecting the gut and are major contributors to bacterial food borne illness, gastrointestinal and systemic diseases for which limited therapeutics are available. Although the pathogenic effects arise from mucosal perturbation, dysregulation of immune cells through mediator release, cell activation or damage are major factors disrupting homeostasis in gut mucosa. Whereas proinflammatory cytokines and chemokines mediate toxic shock induced by staphylococcal enterotoxins, apoptosis and cytotoxic events are responsible for Clostridium perfringens enterotoxin and cholera toxin. Understanding of receptors, signaling pathways and the communication between cells of the gastrointestinal tract, immune and neuroendocrine system will facilitate the development of new therapeutics.

Dr. Teresa Krakauer
Guest Editor

Submission

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Keywords

  • enterotoxins
  • receptor and signaling mechanism
  • mucosal perturbation
  • immunoregulation
  • targeted therapeutics

Published Papers (17 papers)

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Editorial

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Open AccessEditorial Enterotoxins: Microbial Proteins and Host Cell Dysregulation
Toxins 2016, 8(1), 17; doi:10.3390/toxins8010017
Received: 29 December 2015 / Accepted: 4 January 2016 / Published: 8 January 2016
PDF Full-text (182 KB) | HTML Full-text | XML Full-text
Abstract The special issue “Enterotoxins: Microbial Proteins and Host Cell Dysregulation” is comprised of research articles and reviews covering a diverse group of toxins that affect the gut and dysregulate host immune response in mechanistically different ways. [...] Full article

Research

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Open AccessArticle Superantigens Modulate Bacterial Density during Staphylococcus aureus Nasal Colonization
Toxins 2015, 7(5), 1821-1836; doi:10.3390/toxins7051821
Received: 17 December 2014 / Accepted: 15 May 2015 / Published: 22 May 2015
Cited by 4 | PDF Full-text (1396 KB) | HTML Full-text | XML Full-text
Abstract
Superantigens (SAgs) are potent microbial toxins that function to activate large numbers of T cells in a T cell receptor (TCR) Vβ-specific manner, resulting in excessive immune system activation. Staphylococcus aureus possesses a large repertoire of distinct SAgs, and in the context [...] Read more.
Superantigens (SAgs) are potent microbial toxins that function to activate large numbers of T cells in a T cell receptor (TCR) Vβ-specific manner, resulting in excessive immune system activation. Staphylococcus aureus possesses a large repertoire of distinct SAgs, and in the context of host-pathogen interactions, staphylococcal SAg research has focused primarily on the role of these toxins in severe and invasive diseases. However, the contribution of SAgs to colonization by S. aureus remains unclear. We developed a two-week nasal colonization model using SAg-sensitive transgenic mice expressing HLA-DR4, and evaluated the role of SAgs using two well-studied stains of S. aureus. S. aureus Newman produces relatively low levels of staphylococcal enterotoxin A (SEA), and although we did not detect significant TCR-Vβ specific changes during wild-type S. aureus Newman colonization, S. aureus Newman Δsea established transiently higher bacterial loads in the nose. S. aureus COL produces relatively high levels of staphylococcal enterotoxin B (SEB), and colonization with wild-type S. aureus COL resulted in clear Vβ8-specific T cell skewing responses. S. aureus COL Δseb established consistently higher bacterial loads in the nose. These data suggest that staphylococcal SAgs may be involved in regulating bacterial densities during nasal colonization. Full article
Open AccessArticle Binding Studies on Isolated Porcine Small Intestinal Mucosa and in vitro Toxicity Studies Reveal Lack of Effect of C. perfringens Beta-Toxin on the Porcine Intestinal Epithelium
Toxins 2015, 7(4), 1235-1252; doi:10.3390/toxins7041235
Received: 29 January 2015 / Revised: 18 March 2015 / Accepted: 31 March 2015 / Published: 9 April 2015
Cited by 2 | PDF Full-text (3636 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Beta-toxin (CPB) is the essential virulence factor of C. perfringens type C causing necrotizing enteritis (NE) in different hosts. Using a pig infection model, we showed that CPB targets small intestinal endothelial cells. Its effect on the porcine intestinal epithelium, however, could [...] Read more.
Beta-toxin (CPB) is the essential virulence factor of C. perfringens type C causing necrotizing enteritis (NE) in different hosts. Using a pig infection model, we showed that CPB targets small intestinal endothelial cells. Its effect on the porcine intestinal epithelium, however, could not be adequately investigated by this approach. Using porcine neonatal jejunal explants and cryosections, we performed in situ binding studies with CPB. We confirmed binding of CPB to endothelial but could not detect binding to epithelial cells. In contrast, the intact epithelial layer inhibited CPB penetration into deeper intestinal layers. CPB failed to induce cytopathic effects in cultured polarized porcine intestinal epithelial cells (IPEC-J2) and primary jejunal epithelial cells. C. perfringens type C culture supernatants were toxic for cell cultures. This, however, was not inhibited by CPB neutralization. Our results show that, in the porcine small intestine, CPB primarily targets endothelial cells and does not bind to epithelial cells. An intact intestinal epithelial layer prevents CPB diffusion into underlying tissue and CPB alone does not cause direct damage to intestinal epithelial cells. Additional factors might be involved in the early epithelial damage which is needed for CPB diffusion towards its endothelial targets in the small intestine. Full article
Figures

Open AccessArticle Sulfasalazine Attenuates Staphylococcal Enterotoxin B-Induced Immune Responses
Toxins 2015, 7(2), 553-559; doi:10.3390/toxins7020553
Received: 4 December 2014 / Accepted: 27 January 2015 / Published: 13 February 2015
Cited by 2 | PDF Full-text (646 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcal enterotoxin B (SEB) and related exotoxins are important virulence factors produced by Staphylococcus aureus as they cause human diseases such as food poisoning and toxic shock. These toxins bind directly to cells of the immune system resulting in hyperactivation of both [...] Read more.
Staphylococcal enterotoxin B (SEB) and related exotoxins are important virulence factors produced by Staphylococcus aureus as they cause human diseases such as food poisoning and toxic shock. These toxins bind directly to cells of the immune system resulting in hyperactivation of both T lymphocytes and monocytes/macrophages. The excessive release of proinflammatory cytokines from these cells mediates the toxic effects of SEB. This study examined the inhibitory activities of an anti-inflammatory drug, sulfasalazine, on SEB-stimulated human peripheral blood mononuclear cells (PBMC). Sulfasalazine dose-dependently inhibited tumor necrosis factor α, interleukin 1 (IL-1) β, IL-2, IL-6, interferon γ (IFNγ), and various chemotactic cytokines from SEB-stimulated human PBMC. Sulfasalazine also potently blocked SEB-induced T cell proliferation and NFκB activation. These results suggest that sulfasalazine might be useful in mitigating the toxic effects of SEB by blocking SEB-induced host inflammatory cascade and signaling pathways. Full article
Open AccessArticle The Combined Repetitive Oligopeptides of Clostridium difficile Toxin A Counteract Premature Cleavage of the Glucosyl-Transferase Domain by Stabilizing Protein Conformation
Toxins 2014, 6(7), 2162-2176; doi:10.3390/toxins6072162
Received: 22 April 2014 / Revised: 3 July 2014 / Accepted: 4 July 2014 / Published: 22 July 2014
Cited by 4 | PDF Full-text (1589 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Toxin A (TcdA) and B (TcdB) from Clostridium difficile enter host cells by receptor-mediated endocytosis. A prerequisite for proper toxin action is the intracellular release of the glucosyltransferase domain by an inherent cysteine protease, which is allosterically activated by inositol hexaphosphate (IP [...] Read more.
Toxin A (TcdA) and B (TcdB) from Clostridium difficile enter host cells by receptor-mediated endocytosis. A prerequisite for proper toxin action is the intracellular release of the glucosyltransferase domain by an inherent cysteine protease, which is allosterically activated by inositol hexaphosphate (IP6). We found that in in vitro assays, the C-terminally-truncated TcdA1–1065 was more efficient at IP6-induced cleavage compared with full-length TcdA. We hypothesized that the C-terminally-located combined repetitive oligopeptides (CROPs) interact with the N-terminal part of the toxin, thereby preventing autoproteolysis. Glutathione-S-transferase (GST) pull-down assays and microscale thermophoresis confirmed binding between the CROPs and the glucosyltransferase (TcdA1–542) or intermediate (TcdA1102–1847) domain of TcdA, respectively. This interaction between the N- and C-terminus was not found for TcdB. Functional assays revealed that TcdB was more susceptible to inactivation by extracellular IP6-induced cleavage. In vitro autoprocessing and inactivation of TcdA, however, significantly increased, either by acidification of the surrounding milieu or following exchange of its CROP domain by the homologous CROP domain of TcdB. Thus, TcdA CROPs contribute to the stabilization and protection of toxin conformation in addition to function as the main receptor binding domain. Full article
Open AccessArticle Toxic Shock Syndrome Toxin-1-Mediated Toxicity Inhibited by Neutralizing Antibodies Late in the Course of Continual in Vivo and in Vitro Exposure
Toxins 2014, 6(6), 1724-1741; doi:10.3390/toxins6061724
Received: 6 February 2014 / Revised: 7 May 2014 / Accepted: 20 May 2014 / Published: 30 May 2014
Cited by 4 | PDF Full-text (553 KB) | HTML Full-text | XML Full-text
Abstract
Toxic shock syndrome (TSS) results from the host’s overwhelming inflammatory response and cytokine storm mainly due to superantigens (SAgs). There is no effective specific therapy. Application of immunoglobulins has been shown to improve the outcome of the disease and to neutralize SAgs [...] Read more.
Toxic shock syndrome (TSS) results from the host’s overwhelming inflammatory response and cytokine storm mainly due to superantigens (SAgs). There is no effective specific therapy. Application of immunoglobulins has been shown to improve the outcome of the disease and to neutralize SAgs both in vivo and in vitro. However, in most experiments that have been performed, antiserum was either pre-incubated with SAg, or both were applied simultaneously. To mirror more closely the clinical situation, we applied a multiple dose (over five days) lethal challenge in a rabbit model. Treatment with toxic shock syndrome toxin 1 (TSST-1) neutralizing antibody was fully protective, even when administered late in the course of the challenge. Kinetic studies on the effect of superantigen toxins are scarce. We performed in vitro kinetic studies by neutralizing the toxin with antibodies at well-defined time points. T-cell activation was determined by assessing T-cell proliferation (3H-thymidine incorporation), determination of IL-2 release in the cell supernatant (ELISA), and IL-2 gene activation (real-time PCR (RT-PCR)). Here we show that T-cell activation occurs continuously. The application of TSST-1 neutralizing antiserum reduced IL-2 and TNFα release into the cell supernatant, even if added at later time points. Interference with the prolonged stimulation of proinflammatory cytokines is likely to be in vivo relevant, as postexposure treatment protected rabbits against the multiple dose lethal SAg challenge. Our results shed new light on the treatment of TSS by specific antibodies even at late stages of exposure. Full article
Open AccessArticle Assessment of the Functional Regions of the Superantigen Staphylococcal Enterotoxin B
Toxins 2013, 5(10), 1859-1871; doi:10.3390/toxins5101859
Received: 8 August 2013 / Revised: 9 October 2013 / Accepted: 10 October 2013 / Published: 22 October 2013
Cited by 2 | PDF Full-text (387 KB) | HTML Full-text | XML Full-text
Abstract
The functional activity of superantigens is based on capacity of these microbial proteins to bind to both the β-chain of the T cell receptor (TcR) and the major histocompatibility complex (MHC) class II dimer. We have previously shown that a subset of [...] Read more.
The functional activity of superantigens is based on capacity of these microbial proteins to bind to both the β-chain of the T cell receptor (TcR) and the major histocompatibility complex (MHC) class II dimer. We have previously shown that a subset of the bacterial superantigens also binds to a membrane protein, designated p85, which is expressed by renal epithelial cells. This binding activity is a property of SEB, SEC1, 2 and 3, but not SEA, SED, SEE or TSST. The crystal structure of the tri-molecular complex of the superantigen staphylococcal enterotoxin B (SEB) with both the TcR and class II has previously been reported. However, the relative contributions of regions of the superantigen to the overall functional activity of this superantigen remain undefined. In an effort to better define the molecular basis for the interaction of SEB with the TcR β-chain, we report studies here which show the comparative contributions of amino- and carboxy-terminal regions in the superantigen activity of SEB. Recombinant fusion proteins composed of bacterial maltose-binding protein linked to either full-length or truncated toxins in which the 81 N-terminal, or 19 or 34 C-terminal amino acids were deleted, were generated for these studies. This approach provides a determination of the relative strength of the functional activity of the various regions of the superantigen protein. Full article
Open AccessArticle Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses SEB-Induced Lung Inflammation
Toxins 2013, 5(10), 1814-1826; doi:10.3390/toxins5101814
Received: 14 August 2013 / Revised: 3 October 2013 / Accepted: 12 October 2013 / Published: 17 October 2013
Cited by 7 | PDF Full-text (1357 KB) | HTML Full-text | XML Full-text
Abstract
Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential [...] Read more.
Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB. Full article

Review

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Open AccessReview Do the A Subunits Contribute to the Differences in the Toxicity of Shiga Toxin 1 and Shiga Toxin 2?
Toxins 2015, 7(5), 1467-1485; doi:10.3390/toxins7051467
Received: 13 March 2015 / Revised: 23 April 2015 / Accepted: 27 April 2015 / Published: 29 April 2015
Cited by 3 | PDF Full-text (473 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxin producing Escherichia coli O157:H7 (STEC) is one of the leading causes of food-poisoning around the world. Some STEC strains produce Shiga toxin 1 (Stx1) and/or Shiga toxin 2 (Stx2) or variants of either toxin, which are critical for the development [...] Read more.
Shiga toxin producing Escherichia coli O157:H7 (STEC) is one of the leading causes of food-poisoning around the world. Some STEC strains produce Shiga toxin 1 (Stx1) and/or Shiga toxin 2 (Stx2) or variants of either toxin, which are critical for the development of hemorrhagic colitis (HC) or hemolytic uremic syndrome (HUS). Currently, there are no therapeutic treatments for HC or HUS. E. coli O157:H7 strains carrying Stx2 are more virulent and are more frequently associated with HUS, which is the most common cause of renal failure in children in the US. The basis for the increased potency of Stx2 is not fully understood. Shiga toxins belong to the AB5 family of protein toxins with an A subunit, which depurinates a universally conserved adenine residue in the α-sarcin/ricin loop (SRL) of the 28S rRNA and five copies of the B subunit responsible for binding to cellular receptors. Recent studies showed differences in the structure, receptor binding, dependence on ribosomal proteins and pathogenicity of Stx1 and Stx2 and supported a role for the B subunit in differential toxicity. However, the current data do not rule out a potential role for the A1 subunits in the differential toxicity of Stx1 and Stx2. This review highlights the recent progress in understanding the differences in the A1 subunits of Stx1 and Stx2 and their role in defining toxicity. Full article
Open AccessReview Clostridium Perfringens Enterotoxin (CPE) and CPE-Binding Domain (c-CPE) for the Detection and Treatment of Gynecologic Cancers
Toxins 2015, 7(4), 1116-1125; doi:10.3390/toxins7041116
Received: 28 January 2015 / Revised: 17 March 2015 / Accepted: 23 March 2015 / Published: 1 April 2015
Cited by 6 | PDF Full-text (411 KB) | HTML Full-text | XML Full-text
Abstract
Clostridium perfringens enterotoxin (CPE) is a three-domain polypeptide, which binds to Claudin-3 and Claudin-4 with high affinity. Because these receptors are highly differentially expressed in many human tumors, claudin-3 and claudin-4 may provide an efficient molecular tool to specifically identify and target [...] Read more.
Clostridium perfringens enterotoxin (CPE) is a three-domain polypeptide, which binds to Claudin-3 and Claudin-4 with high affinity. Because these receptors are highly differentially expressed in many human tumors, claudin-3 and claudin-4 may provide an efficient molecular tool to specifically identify and target biologically aggressive human cancer cells for CPE-specific binding and cytolysis. In this review we will discuss these surface proteins as targets for the detection and treatment of chemotherapy-resistant gynecologic malignancies overexpressing claudin-3 and -4 using CPE-based theranostic agents. We will also discuss the use of fluorescent c-CPE peptide in the operative setting for real time detection of micro-metastatic tumors during surgery and review the potential role of CPE in other medical applications. Full article
Open AccessReview Cholera Toxin B: One Subunit with Many Pharmaceutical Applications
Toxins 2015, 7(3), 974-996; doi:10.3390/toxins7030974
Received: 5 February 2015 / Accepted: 16 March 2015 / Published: 20 March 2015
Cited by 8 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
Cholera, a waterborne acute diarrheal disease caused by Vibrio cholerae, remains prevalent in underdeveloped countries and is a serious health threat to those living in unsanitary conditions. The major virulence factor is cholera toxin (CT), which consists of two subunits: the [...] Read more.
Cholera, a waterborne acute diarrheal disease caused by Vibrio cholerae, remains prevalent in underdeveloped countries and is a serious health threat to those living in unsanitary conditions. The major virulence factor is cholera toxin (CT), which consists of two subunits: the A subunit (CTA) and the B subunit (CTB). CTB is a 55 kD homopentameric, non-toxic protein binding to the GM1 ganglioside on mammalian cells with high affinity. Currently, recombinantly produced CTB is used as a component of an internationally licensed oral cholera vaccine, as the protein induces potent humoral immunity that can neutralize CT in the gut. Additionally, recent studies have revealed that CTB administration leads to the induction of anti-inflammatory mechanisms in vivo. This review will cover the potential of CTB as an immunomodulatory and anti-inflammatory agent. We will also summarize various recombinant expression systems available for recombinant CTB bioproduction. Full article
Open AccessReview Recent Insights into Clostridium perfringens Beta-Toxin
Toxins 2015, 7(2), 396-406; doi:10.3390/toxins7020396
Received: 20 December 2014 / Revised: 15 January 2015 / Accepted: 29 January 2015 / Published: 3 February 2015
Cited by 6 | PDF Full-text (431 KB) | HTML Full-text | XML Full-text
Abstract
Clostridium perfringens beta-toxin is a key mediator of necrotizing enterocolitis and enterotoxemia. It is a pore-forming toxin (PFT) that exerts cytotoxic effect. Experimental investigation using piglet and rabbit intestinal loop models and a mouse infection model apparently showed that beta-toxin is the [...] Read more.
Clostridium perfringens beta-toxin is a key mediator of necrotizing enterocolitis and enterotoxemia. It is a pore-forming toxin (PFT) that exerts cytotoxic effect. Experimental investigation using piglet and rabbit intestinal loop models and a mouse infection model apparently showed that beta-toxin is the important pathogenic factor of the organisms. The toxin caused the swelling and disruption of HL-60 cells and formed a functional pore in the lipid raft microdomains of sensitive cells. These findings represent significant progress in the characterization of the toxin with knowledge on its biological features, mechanism of action and structure-function having been accumulated. Our aims here are to review the current progresses in our comprehension of the virulence of C. perfringens type C and the character, biological feature and structure-function of beta-toxin. Full article
Open AccessReview Clostridium and Bacillus Binary Enterotoxins: Bad for the Bowels, and Eukaryotic Being
Toxins 2014, 6(9), 2626-2656; doi:10.3390/toxins6092626
Received: 1 August 2014 / Revised: 22 August 2014 / Accepted: 27 August 2014 / Published: 5 September 2014
Cited by 7 | PDF Full-text (523 KB) | HTML Full-text | XML Full-text
Abstract
Some pathogenic spore-forming bacilli employ a binary protein mechanism for intoxicating the intestinal tracts of insects, animals, and humans. These Gram-positive bacteria and their toxins include Clostridium botulinum (C2 toxin), Clostridium difficile (C. difficile toxin or CDT), Clostridium perfringens (ι-toxin and [...] Read more.
Some pathogenic spore-forming bacilli employ a binary protein mechanism for intoxicating the intestinal tracts of insects, animals, and humans. These Gram-positive bacteria and their toxins include Clostridium botulinum (C2 toxin), Clostridium difficile (C. difficile toxin or CDT), Clostridium perfringens (ι-toxin and binary enterotoxin, or BEC), Clostridium spiroforme (C. spiroforme toxin or CST), as well as Bacillus cereus (vegetative insecticidal protein or VIP). These gut-acting proteins form an AB complex composed of ADP-ribosyl transferase (A) and cell-binding (B) components that intoxicate cells via receptor-mediated endocytosis and endosomal trafficking. Once inside the cytosol, the A components inhibit normal cell functions by mono-ADP-ribosylation of globular actin, which induces cytoskeletal disarray and death. Important aspects of each bacterium and binary enterotoxin will be highlighted in this review, with particular focus upon the disease process involving the biochemistry and modes of action for each toxin. Full article
Open AccessReview Staphylococcal enterotoxins in the Etiopathogenesis of Mucosal Autoimmunity within the Gastrointestinal Tract
Toxins 2014, 6(5), 1471-1489; doi:10.3390/toxins6051471
Received: 18 December 2013 / Revised: 18 April 2014 / Accepted: 22 April 2014 / Published: 25 April 2014
Cited by 6 | PDF Full-text (829 KB) | HTML Full-text | XML Full-text
Abstract
The staphylococcal enterotoxins (SEs) are the products of Staphylococcus aureus and are recognized as the causative agents of classical food poisoning in humans following the consumption of contaminated food. While illness evoked by ingestion of the SE or its producer organism in [...] Read more.
The staphylococcal enterotoxins (SEs) are the products of Staphylococcus aureus and are recognized as the causative agents of classical food poisoning in humans following the consumption of contaminated food. While illness evoked by ingestion of the SE or its producer organism in tainted food are often self-limited, our current understanding regarding the evolution of S. aureus provokes the utmost concern. The organism and its associated toxins, has been implicated in a wide variety of disease states including infections of the skin, heart, sinuses, inflammatory gastrointestinal disease, toxic shock, and Sudden Infant Death Syndrome. The intricate relationship between the various subsets of immunocompetent T cells and accessory cells and the ingested material found within the gastrointestinal tract present daunting challenges to the maintenance of immunologic homeostasis. Dysregulation of the intricate balances within this environment has the potential for extreme consequences within the host, some of which are long-lived. The focus of this review is to evaluate the relevance of staphylococcal enterotoxin in the context of mucosal immunity, and the underlying mechanisms that contribute to the pathogenesis of gastrointestinal autoimmune disease. Full article
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Open AccessReview Soluble T Cell Receptor Vβ Domains Engineered for High-Affinity Binding to Staphylococcal or Streptococcal Superantigens
Toxins 2014, 6(2), 556-574; doi:10.3390/toxins6020556
Received: 16 December 2013 / Revised: 21 January 2014 / Accepted: 22 January 2014 / Published: 28 January 2014
Cited by 6 | PDF Full-text (761 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcus aureus and group A Streptococcus secrete a collection of toxins called superantigens (SAgs), so-called because they stimulate a large fraction of an individual’s T cells. One consequence of this hyperactivity is massive cytokine release leading to severe tissue inflammation and, in [...] Read more.
Staphylococcus aureus and group A Streptococcus secrete a collection of toxins called superantigens (SAgs), so-called because they stimulate a large fraction of an individual’s T cells. One consequence of this hyperactivity is massive cytokine release leading to severe tissue inflammation and, in some cases, systemic organ failure and death. The molecular basis of action involves the binding of the SAg to both a T cell receptor (TCR) on a T cell and a class II product of the major histocompatibility complex (MHC) on an antigen presenting cell. This cross-linking leads to aggregation of the TCR complex and signaling. A common feature of SAgs is that they bind with relatively low affinity to the variable region (V) of the beta chain of the TCR. Despite this low affinity binding, SAgs are very potent, as each T cell requires only a small fraction of their receptors to be bound in order to trigger cytokine release. To develop high-affinity agents that could neutralize the activity of SAgs, and facilitate the development of detection assays, soluble forms of the Vβ regions have been engineered to affinities that are up to 3 million-fold higher for the SAg. Over the past decade, six different Vβ regions against SAgs from S. aureus (SEA, SEB, SEC3, TSST-1) or S. pyogenes (SpeA and SpeC) have been engineered for high-affinity using yeast display and directed evolution. Here we review the engineering of these high-affinity Vβ proteins, structural features of the six different SAgs and the Vβ proteins, and the specific properties of the engineered Vβ regions that confer high-affinity and specificity for their SAg ligands. Full article
Open AccessReview Clostridium perfringens Epsilon Toxin: A Malevolent Molecule for Animals and Man?
Toxins 2013, 5(11), 2138-2160; doi:10.3390/toxins5112138
Received: 1 October 2013 / Revised: 30 October 2013 / Accepted: 31 October 2013 / Published: 12 November 2013
Cited by 15 | PDF Full-text (334 KB) | HTML Full-text | XML Full-text
Abstract
Clostridium perfringens is a prolific, toxin-producing anaerobe causing multiple diseases in humans and animals. One of these toxins is epsilon, a 33 kDa protein produced by Clostridium perfringens (types B and D) that induces fatal enteric disease of goats, sheep and cattle. [...] Read more.
Clostridium perfringens is a prolific, toxin-producing anaerobe causing multiple diseases in humans and animals. One of these toxins is epsilon, a 33 kDa protein produced by Clostridium perfringens (types B and D) that induces fatal enteric disease of goats, sheep and cattle. Epsilon toxin (Etx) belongs to the aerolysin-like toxin family. It contains three distinct domains, is proteolytically-activated and forms oligomeric pores on cell surfaces via a lipid raft-associated protein(s). Vaccination controls Etx-induced disease in the field. However, therapeutic measures are currently lacking. This review initially introduces C. perfringens toxins, subsequently focusing upon the Etx and its biochemistry, disease characteristics in various animals that include laboratory models (in vitro and in vivo), and finally control mechanisms (vaccines and therapeutics). Full article
Open AccessReview Update on Staphylococcal Superantigen-Induced Signaling Pathways and Therapeutic Interventions
Toxins 2013, 5(9), 1629-1654; doi:10.3390/toxins5091629
Received: 8 July 2013 / Revised: 13 September 2013 / Accepted: 13 September 2013 / Published: 24 September 2013
Cited by 19 | PDF Full-text (476 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcal enterotoxin B (SEB) and related bacterial toxins cause diseases in humans and laboratory animals ranging from food poisoning, acute lung injury to toxic shock. These superantigens bind directly to the major histocompatibility complex class II molecules on antigen-presenting cells and specific [...] Read more.
Staphylococcal enterotoxin B (SEB) and related bacterial toxins cause diseases in humans and laboratory animals ranging from food poisoning, acute lung injury to toxic shock. These superantigens bind directly to the major histocompatibility complex class II molecules on antigen-presenting cells and specific Vβ regions of T-cell receptors (TCR), resulting in rapid hyper-activation of the host immune system. In addition to TCR and co-stimulatory signals, proinflammatory mediators activate signaling pathways culminating in cell-stress response, activation of NFκB and mammalian target of rapamycin (mTOR). This article presents a concise review of superantigen-activated signaling pathways and focuses on the therapeutic challenges against bacterial superantigens. Full article

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