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Topical Collection "Shiga Toxins"

A topical collection in Toxins (ISSN 2072-6651). This collection belongs to the section "Bacterial Toxins".

Editors

Collection Editor
Prof. Dr. Gerald B. Koudelka

Department of Biological Sciences, University at Buffalo, Buffalo, NY 14260, USA
Website | E-Mail
Phone: 716-645-4940
Interests: Evolution, distribution and role of exotoxin-encoding bacteria and phages in the environment; Identification and characterization of bacterial anti-predator defense mechanisms; Biotic and abiotic factors that govern the stability lambdoid prophages; DNA structure effects on protein-DNA Interactions
Collection Editor
Dr. Steven A Mauro

Gannon University,109 University Square, Erie, PA 16501, USA
Website | E-Mail
Interests: Factors governing STEC in the environment; Biotic and abiotic factors influencing water quality; Bacterial and viral distribution in freshwater; The emergence of harmful algal blooms in aquatic environments
Former Guest Editor
Prof. Dr. Clifford A. Lingwood

Division of Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
Website | E-Mail
Fax: +1 416 8135993

Topical Collection Information

Dear Colleagues,

Shiga toxins are the main virulence factor of a group of Shiga toxin-encoding E. coli (STEC) strains that cause severe human diseases, such as hemorrhagic colitis and hemolytic uremic syndrome. Shiga toxin is implicated in over 10,000 cases of human illness annually in the United States alone, and infection with STEC carries a mortality rate as high as 10%. Shiga toxin intoxication is the number one cause of acute renal failure in children. Alarmingly, the incidence of Shiga toxin-related illness is increasing; in the two decades following its emergence, outbreaks of disease caused by STEC increased >20-fold. In addition to contaminated food, STEC outbreaks are increasingly associated with environmental contamination of water. Therefore, factors that impact the environmental survival of STEC clearly have a role in regulating the transmission of these pathogens to humans.

The Shiga toxin family is divided into several toxin subtypes, each of which is apparently differentially involved in causing human disease. Shiga toxins are encoded by a family of bacteriophage that are related to the well-characterized nontoxic coliphage λ. A recent expansion in the numbers of available STEC genome sequences and Shiga toxin encoding phages indicate that both the families of Stx-encoding phage and the bacteria that harbor them are large and display a much higher diversity than previously thought. Phage diversity may play an important role in the dissemination of Shiga-toxin genes and the emergence of new STEC strains, but also in the regulation of Shiga toxin production.

Prof. Dr. Gerald B. Koudelka
Dr. Steven A Mauro
Collection Editor

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"A similar collection Shiga Toxins can be found at https://www.mdpi.com/journal/toxins/special_issues/shiga

Keywords

  • Shiga toxin
  • Bacteria
  • Bacteriophage
  • STEC
  • E. coli O157
  • Virulence
  • Diversity

Related Special Issue

Published Papers (18 papers)

2018

Jump to: 2017, 2016, 2015, 2011

Open AccessArticle Human Recombinant Fab Fragment Neutralizes Shiga Toxin Type 2 Cytotoxic Effects in vitro and in vivo
Toxins 2018, 10(12), 508; https://doi.org/10.3390/toxins10120508
Received: 25 September 2018 / Revised: 24 November 2018 / Accepted: 28 November 2018 / Published: 2 December 2018
Cited by 1 | PDF Full-text (2196 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxin (Stx) producing Escherichia coli (STEC) is responsible for causing hemolytic uremic syndrome (HUS), a life-threatening thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and acute renal failure after bacterially induced hemorrhagic diarrhea. Until now, there has been neither an effective treatment nor [...] Read more.
Shiga toxin (Stx) producing Escherichia coli (STEC) is responsible for causing hemolytic uremic syndrome (HUS), a life-threatening thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and acute renal failure after bacterially induced hemorrhagic diarrhea. Until now, there has been neither an effective treatment nor method of prevention for the deleterious effects caused by Stx intoxication. Antibodies are well recognized as affinity components of therapeutic drugs; thus, a previously obtained recombinant human FabC11:Stx2 fragment was used to neutralize Stx2 in vitro in a Vero cell viability assay. Herein, we demonstrated that this fragment neutralized, in a dose-dependent manner, the cytotoxic effects of Stx2 on human glomerular endothelial cells, on human proximal tubular epithelial cells, and prevented the morphological alterations induced by Stx2. FabC11:Stx2 protected mice from a lethal dose of Stx2 by toxin-antibody pre-incubation. Altogether, our results show the ability of a new encouraging molecule to prevent Stx-intoxication symptoms during STEC infection. Full article
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2017

Jump to: 2018, 2016, 2015, 2011

Open AccessEditor’s ChoiceArticle Shiga Toxin Glycosphingolipid Receptors in Human Caco-2 and HCT-8 Colon Epithelial Cell Lines
Toxins 2017, 9(11), 338; https://doi.org/10.3390/toxins9110338
Received: 26 September 2017 / Revised: 11 October 2017 / Accepted: 19 October 2017 / Published: 25 October 2017
Cited by 7 | PDF Full-text (4094 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Shiga toxins (Stxs) released by enterohemorrhagic Escherichia coli (EHEC) into the human colon are the causative agents for fatal outcome of EHEC infections. Colon epithelial Caco-2 and HCT-8 cells are widely used for investigating Stx-mediated intestinal cytotoxicity. Only limited data are available regarding [...] Read more.
Shiga toxins (Stxs) released by enterohemorrhagic Escherichia coli (EHEC) into the human colon are the causative agents for fatal outcome of EHEC infections. Colon epithelial Caco-2 and HCT-8 cells are widely used for investigating Stx-mediated intestinal cytotoxicity. Only limited data are available regarding precise structures of their Stx receptor glycosphingolipids (GSLs) globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), and lipid raft association. In this study we identified Gb3Cer and Gb4Cer lipoforms of serum-free cultivated Caco-2 and HCT-8 cells, chiefly harboring ceramide moieties composed of sphingosine (d18:1) and C16:0, C22:0 or C24:0/C24:1 fatty acid. The most significant difference between the two cell lines was the prevalence of Gb3Cer with C16 fatty acid in HCT-8 and Gb4Cer with C22–C24 fatty acids in Caco-2 cells. Lipid compositional analysis of detergent-resistant membranes (DRMs), which were used as lipid raft-equivalents, indicated slightly higher relative content of Stx receptor Gb3Cer in DRMs of HCT-8 cells when compared to Caco-2 cells. Cytotoxicity assays revealed substantial sensitivity towards Stx2a for both cell lines, evidencing little higher susceptibility of Caco-2 cells versus HCT-8 cells. Collectively, Caco-2 and HCT-8 cells express a plethora of different receptor lipoforms and are susceptible towards Stx2a exhibiting somewhat lower sensitivity when compared to Vero cells. Full article
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Open AccessArticle Soluble CD40 Ligand and Oxidative Response Are Reciprocally Stimulated during Shiga Toxin-Associated Hemolytic Uremic Syndrome
Toxins 2017, 9(11), 331; https://doi.org/10.3390/toxins9110331
Received: 17 August 2017 / Revised: 29 September 2017 / Accepted: 15 October 2017 / Published: 25 October 2017
Cited by 1 | PDF Full-text (6522 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxin (Stx), produced by Escherichia coli, is the main pathogenic factor of diarrhea-associated hemolytic uremic syndrome (HUS), which is characterized by the obstruction of renal microvasculature by platelet-fibrin thrombi. It is well known that the oxidative imbalance generated by Stx induces [...] Read more.
Shiga toxin (Stx), produced by Escherichia coli, is the main pathogenic factor of diarrhea-associated hemolytic uremic syndrome (HUS), which is characterized by the obstruction of renal microvasculature by platelet-fibrin thrombi. It is well known that the oxidative imbalance generated by Stx induces platelet activation, contributing to thrombus formation. Moreover, activated platelets release soluble CD40 ligand (sCD40L), which in turn contributes to oxidative imbalance, triggering the release of reactive oxidative species (ROS) on various cellular types. The aim of this work was to determine if the interaction between the oxidative response and platelet-derived sCD40L, as consequence of Stx-induced endothelium damage, participates in the pathogenic mechanism during HUS. Activated human glomerular endothelial cells (HGEC) by Stx2 induced platelets to adhere to them. Although platelet adhesion did not contribute to endothelial damage, high levels of sCD40L were released to the medium. The release of sCD40L by activated platelets was inhibited by antioxidant treatment. Furthermore, we found increased levels of sCD40L in plasma from HUS patients, which were also able to trigger the respiratory burst in monocytes in a sCD40L-dependent manner. Thus, we concluded that platelet-derived sCD40L and the oxidative response are reciprocally stimulated during Stx2-associated HUS. This process may contribute to the evolution of glomerular occlusion and the microangiopathic lesions. Full article
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Open AccessArticle Ouabain Protects Human Renal Cells against the Cytotoxic Effects of Shiga Toxin Type 2 and Subtilase Cytotoxin
Received: 20 June 2017 / Revised: 10 July 2017 / Accepted: 12 July 2017 / Published: 18 July 2017
Cited by 2 | PDF Full-text (5431 KB) | HTML Full-text | XML Full-text
Abstract
Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children. The majority of cases are associated with Shiga toxin (Stx)-producing Escherichia coli (STEC). In Argentina, HUS is endemic and presents the highest incidence rate in the [...] Read more.
Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children. The majority of cases are associated with Shiga toxin (Stx)-producing Escherichia coli (STEC). In Argentina, HUS is endemic and presents the highest incidence rate in the world. STEC strains expressing Stx type 2 (Stx2) are responsible for the most severe cases of this pathology. Subtilase cytotoxin (SubAB) is another STEC virulence factor that may contribute to HUS pathogenesis. To date, neither a licensed vaccine nor effective therapy for HUS is available for humans. Considering that Ouabain (OUA) may prevent the apoptosis process, in this study we evaluated if OUA is able to avoid the damage caused by Stx2 and SubAB on human glomerular endothelial cells (HGEC) and the human proximal tubule epithelial cell (HK-2) line. HGEC and HK-2 were pretreated with OUA and then incubated with the toxins. OUA protected the HGEC viability from Stx2 and SubAB cytotoxic effects, and also prevented the HK-2 viability from Stx2 effects. The protective action of OUA on HGEC and HK-2 was associated with a decrease in apoptosis and an increase in cell proliferation. Our data provide evidence that OUA could be considered as a therapeutic strategy to avoid the renal damage that precedes HUS. Full article
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Open AccessArticle Efficacy of Urtoxazumab (TMA-15 Humanized Monoclonal Antibody Specific for Shiga Toxin 2) Against Post-Diarrheal Neurological Sequelae Caused by Escherichia coli O157:H7 Infection in the Neonatal Gnotobiotic Piglet Model
Received: 1 November 2016 / Revised: 13 January 2017 / Accepted: 19 January 2017 / Published: 26 January 2017
Cited by 1 | PDF Full-text (1221 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Enterohemorrhagic Escherichia coli (EHEC) is the most common cause of hemorrhagic colitis and hemolytic uremic syndrome in human patients, with brain damage and dysfunction the main cause of acute death. We evaluated the efficacy of urtoxazumab (TMA-15, Teijin Pharma Limited), a humanized monoclonal [...] Read more.
Enterohemorrhagic Escherichia coli (EHEC) is the most common cause of hemorrhagic colitis and hemolytic uremic syndrome in human patients, with brain damage and dysfunction the main cause of acute death. We evaluated the efficacy of urtoxazumab (TMA-15, Teijin Pharma Limited), a humanized monoclonal antibody against Shiga toxin (Stx) 2 for the prevention of brain damage, dysfunction, and death in a piglet EHEC infection model. Forty-five neonatal gnotobiotic piglets were inoculated orally with 3 × 109 colony-forming units of EHEC O157:H7 strain EDL933 (Stx1+, Stx2+) when 22–24 h old. At 24 h post-inoculation, piglets were intraperitoneally administered placebo or TMA-15 (0.3, 1.0 or 3.0 mg/kg body weight). Compared to placebo (n = 10), TMA-15 (n = 35) yielded a significantly greater probability of survival, length of survival, and weight gain (p <0.05). The efficacy of TMA-15 against brain lesions and death was 62.9% (p = 0.0004) and 71.4% (p = 0.0004), respectively. These results suggest that TMA-15 may potentially prevent or reduce vascular necrosis and infarction of the brain attributable to Stx2 in human patients acutely infected with EHEC. However, we do not infer that TMA-15 treatment will completely protect human patients infected with EHEC O157:H7 strains that produce both Stx1 and Stx2. Full article
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2016

Jump to: 2018, 2017, 2015, 2011

Open AccessArticle A Topographical Atlas of Shiga Toxin 2e Receptor Distribution in the Tissues of Weaned Piglets
Toxins 2016, 8(12), 357; https://doi.org/10.3390/toxins8120357
Received: 21 October 2016 / Revised: 21 November 2016 / Accepted: 28 November 2016 / Published: 30 November 2016
Cited by 2 | PDF Full-text (5714 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Shiga toxin (Stx) 2e of Stx-producing Escherichia coli (STEC) is the primary virulence factor in the development of pig edema disease shortly after weaning. Stx2e binds to the globo-series glycosphingolipids (GSLs) globotriaosylceramide (Gb3Cer, Galα1-4Galβ1-4Glcβ1-1Cer) and globotetraosylceramide (Gb4Cer, GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1Cer), the latter acting as the [...] Read more.
Shiga toxin (Stx) 2e of Stx-producing Escherichia coli (STEC) is the primary virulence factor in the development of pig edema disease shortly after weaning. Stx2e binds to the globo-series glycosphingolipids (GSLs) globotriaosylceramide (Gb3Cer, Galα1-4Galβ1-4Glcβ1-1Cer) and globotetraosylceramide (Gb4Cer, GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1Cer), the latter acting as the preferential Stx2e receptor. We determined Stx receptor profiles of 25 different tissues of a male and a female weaned piglet using immunochemical solid phase binding assays combined with mass spectrometry. All probed tissues harbored GSL receptors, ranging from high (category I) over moderate (category II) to low content (category III). Examples of Gb4Cer expression in category I tissues are small intestinal ileum, kidney pelvis and whole blood, followed by colon, small intestinal duodenum and jejunum belonging to category II, and kidney cortex, cerebrum and cerebellum as members of category III organs holding true for both genders. Dominant Gb3Cer and Gb4Cer lipoforms were those with ceramides carrying constant sphingosine (d18:1) and a variable C16:0, C22:0 or C24:1/C24:0 fatty acid. From the mapping data, we created a topographical atlas for Stx2e receptors in piglet tissues and organs, which might be helpful to further investigations on the molecular and cellular mechanisms that underlie infections of Stx2e-producing STEC in pigs and their zoonotic potential for humans. Full article
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Open AccessFeature PaperArticle Mechanisms that Determine the Differential Stability of Stx+ and Stx Lysogens
Received: 19 February 2016 / Revised: 23 March 2016 / Accepted: 25 March 2016 / Published: 31 March 2016
Cited by 7 | PDF Full-text (1800 KB) | HTML Full-text | XML Full-text
Abstract
Phages 933W, BAA2326, 434, and λ are evolutionarily-related temperate lambdoid phages that infect Escherichia coli. Although these are highly-similar phages, BAA2326 and 933W naturally encode Shiga toxin 2 (Stx+), but phage 434 and λ do not (Stx). Previous [...] Read more.
Phages 933W, BAA2326, 434, and λ are evolutionarily-related temperate lambdoid phages that infect Escherichia coli. Although these are highly-similar phages, BAA2326 and 933W naturally encode Shiga toxin 2 (Stx+), but phage 434 and λ do not (Stx). Previous reports suggest that the 933W Stx+ prophage forms less stable lysogens in E. coli than does the Stx prophages λ, P22, and 434. The higher spontaneous induction frequency of the Stx+ prophage may be correlated with both virulence and dispersion of the Stx2-encoding phage. Here, we examined the hypothesis that lysogen instability is a common feature of Stx+ prophages. We found in both the absence and presence of prophage inducers (DNA damaging agents, salts), the Stx+ prophages induce at higher frequencies than do Stx prophages. The observed instability of Stx+ prophages does not appear to be the result of any differences in phage development properties between Stx+ and Stx phages. Our results indicate that differential stability of Stx+ and Stx prophages results from both RecA-dependent and RecA-independent effects on the intracellular concentration of the respective cI repressors. Full article
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Open AccessFeature PaperReview Shiga Toxins as Multi-Functional Proteins: Induction of Host Cellular Stress Responses, Role in Pathogenesis and Therapeutic Applications
Received: 22 October 2015 / Revised: 25 February 2016 / Accepted: 29 February 2016 / Published: 17 March 2016
Cited by 25 | PDF Full-text (1448 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria Shigella dysenteriae serotype 1 and select serotypes of Escherichia coli are primary virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications, such as hemolytic uremic syndrome and central nervous system [...] Read more.
Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria Shigella dysenteriae serotype 1 and select serotypes of Escherichia coli are primary virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications, such as hemolytic uremic syndrome and central nervous system abnormalities. Current therapeutic options to treat patients infected with toxin-producing bacteria are limited. The structures of Stxs, toxin-receptor binding, intracellular transport and the mode of action of the toxins have been well defined. However, in the last decade, numerous studies have demonstrated that in addition to being potent protein synthesis inhibitors, Stxs are also multifunctional proteins capable of activating multiple cell stress signaling pathways, which may result in apoptosis, autophagy or activation of the innate immune response. Here, we briefly present the current understanding of Stx-activated signaling pathways and provide a concise review of therapeutic applications to target tumors by engineering the toxins. Full article
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Open AccessFeature PaperArticle Vitamin B12 Uptake by the Gut Commensal Bacteria Bacteroides thetaiotaomicron Limits the Production of Shiga Toxin by Enterohemorrhagic Escherichia coli
Received: 14 October 2015 / Revised: 17 December 2015 / Accepted: 29 December 2015 / Published: 5 January 2016
Cited by 11 | PDF Full-text (896 KB) | HTML Full-text | XML Full-text
Abstract
Enterohemorrhagic Escherichia coli (EHEC) are foodborne pathogens responsible for the development of bloody diarrhea and renal failure in humans. Many environmental factors have been shown to regulate the production of Shiga toxin 2 (Stx2), the main virulence factor of EHEC. Among them, soluble [...] Read more.
Enterohemorrhagic Escherichia coli (EHEC) are foodborne pathogens responsible for the development of bloody diarrhea and renal failure in humans. Many environmental factors have been shown to regulate the production of Shiga toxin 2 (Stx2), the main virulence factor of EHEC. Among them, soluble factors produced by human gut microbiota and in particular, by the predominant species Bacteroides thetaiotaomicron (B. thetaiotaomicron), inhibit Stx2 gene expression. In this study, we investigated the molecular mechanisms underlying the B. thetaiotaomicron-dependent inhibition of Stx2 production by EHEC. We determined that Stx2-regulating molecules are resistant to heat treatment but do not correspond to propionate and acetate, two short-chain fatty acids produced by B. thetaiotaomicron. Moreover, screening of a B. thetaiotaomicron mutant library identified seven mutants that do not inhibit Stx2 synthesis by EHEC. One mutant has impaired production of BtuB, an outer membrane receptor for vitamin B12. Together with restoration of Stx2 level after vitamin B12 supplementation, these data highlight vitamin B12 as a molecule produced by gut microbiota that modulates production of a key virulence factor of EHEC and consequently may affect the outcome of an infection. Full article
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2015

Jump to: 2018, 2017, 2016, 2011

Open AccessArticle The Effects of Shiga Toxin 1, 2 and Their Subunits on Cytokine and Chemokine Expression by Human Macrophage-Like THP-1 Cells
Toxins 2015, 7(10), 4054-4066; https://doi.org/10.3390/toxins7104054
Received: 8 June 2015 / Revised: 19 September 2015 / Accepted: 24 September 2015 / Published: 9 October 2015
Cited by 7 | PDF Full-text (275 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Infection by Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC) results in severe diarrhea, hemorrhagic colitis, and, occasionally, hemolytic-uremic syndrome (HUS). HUS is associated with an increase in pro-inflammatory cytokines and chemokines, many of which are produced by macrophages in the kidneys, indicating that [...] Read more.
Infection by Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC) results in severe diarrhea, hemorrhagic colitis, and, occasionally, hemolytic-uremic syndrome (HUS). HUS is associated with an increase in pro-inflammatory cytokines and chemokines, many of which are produced by macrophages in the kidneys, indicating that localized host innate immunity likely plays a role in renal pathogenesis. EHEC serotypes may express one or two classes of serologically defined but structurally and functionally-related Shiga toxins called Stx1 and Stx2. Of these, Stx2 appears to be linked to higher rates of HUS than Stx1. To investigate a possible reason for this, we exposed human macrophage-like THP-1 cells to Stx1 or Stx2 and then used the Luminex multiplex system to assess cytokine/chemokine concentrations in culture supernatant solutions. This analysis revealed that, relative to Stx1, Stx2 significantly caused increased expression of GRO, G-CSF, IL-1β, IL-8 and TNFα in macrophage-like THP-1 cells. This was determined to not be due to a difference in cytotoxicity since both Stx1 and Stx2 displayed similar cytotoxic activities on macrophage-like THP-1 cells. These observations indicate that, in vitro, Stx2 can provoke a greater pro-inflammatory response than Stx1 in macrophages and provides a possible partial explanation for higher rates of HUS in patients infected with EHEC strains expressing Stx2. To begin to determine a mechanism for Shiga toxin-mediated cytokine production, we exposed macrophage-like THP-1 cells to Stx1 or Stx2 A and B subunits. Luminex analysis of cytokines in cell culture supernatant solutions demonstrated that neither subunit alone induced a cytokine response in THP-1 cells. Full article
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Open AccessArticle UV-Sensitivity of Shiga Toxin-Converting Bacteriophage Virions Φ24B, 933W, P22, P27 and P32
Toxins 2015, 7(9), 3727-3739; https://doi.org/10.3390/toxins7093727
Received: 30 August 2015 / Revised: 14 September 2015 / Accepted: 16 September 2015 / Published: 21 September 2015
Cited by 5 | PDF Full-text (1383 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxin-converting bacteriophages (Stx phages) are present as prophages in Shiga toxin-producing Escherichia coli (STEC) strains. Theses phages can be transmitted to previously non-pathogenic E. coli cells making them potential producers of Shiga toxins, as they bear genes for these toxins in their [...] Read more.
Shiga toxin-converting bacteriophages (Stx phages) are present as prophages in Shiga toxin-producing Escherichia coli (STEC) strains. Theses phages can be transmitted to previously non-pathogenic E. coli cells making them potential producers of Shiga toxins, as they bear genes for these toxins in their genomes. Therefore, sensitivity of Stx phage virions to various conditions is important in both natural processes of spreading of these viruses and potential prophylactic control of appearance of novel pathogenic E. coli strains. In this report we provide evidence that virions of Stx phages are significantly more sensitive to UV irradiation than bacteriophage λ. Following UV irradiation of Stx virions at the dose of 50 J/m2, their infectivity dropped by 1–3 log10, depending on the kind of phage. Under these conditions, a considerable release of phage DNA from virions was observed, and electron microscopy analyses indicated a large proportion of partially damaged virions. Infection of E. coli cells with UV-irradiated Stx phages resulted in significantly decreased levels of expression of N and cro genes, crucial for lytic development. We conclude that inactivation of Stx virions caused by relatively low dose of UV light is due to damage of capsids that prevents effective infection of the host cells. Full article
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Open AccessArticle Reduced Toxicity of Shiga Toxin (Stx) Type 2c in Mice Compared to Stx2d Is Associated with Instability of Stx2c Holotoxin
Toxins 2015, 7(6), 2306-2320; https://doi.org/10.3390/toxins7062306
Received: 9 April 2015 / Revised: 28 May 2015 / Accepted: 16 June 2015 / Published: 23 June 2015
Cited by 2 | PDF Full-text (763 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxin (Stx) is an AB5 ribotoxin made by Stx-producing Escherichia coli (STEC). These organisms cause diarrhea, hemorrhagic colitis and the hemolytic uremic syndrome. STEC make two types of Stxs, Stx1 and/or Stx2. Stx2 has one prototype (a) and six subtypes (b–g), [...] Read more.
Shiga toxin (Stx) is an AB5 ribotoxin made by Stx-producing Escherichia coli (STEC). These organisms cause diarrhea, hemorrhagic colitis and the hemolytic uremic syndrome. STEC make two types of Stxs, Stx1 and/or Stx2. Stx2 has one prototype (a) and six subtypes (b–g), but only STEC that make Stx2a, and/or Stx2c, or Stx2d are associated with severe disease. However, Stx2c is about 10-fold less toxic than Stx2d in vivo despite only two amino acid differences in the A subunit at positions 291 and 297. We made mutations at these two sites to create intermediate toxins between Stx2c and Stx2d, and determined the 50% cytotoxic dose on Vero cells before and after heat treatment, and the 50% lethal dose in mice of the toxins. We found that serine 291 was associated with increased toxicity in vivo and that either amino acid change from that in Stx2c to that in Stx2d increased heat stability. We also assessed the secondary structure of Stx2c and Stx2d by circular dichroism (CD) spectroscopy. The CD studies suggest that Stx2c has a less-ordered secondary structure than Stx2d. We conclude that both amino acids at positions 291 and 297 in Stx2c contribute to its decreased stability and in vivo toxicity compared to Stx2d. Full article
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Open AccessArticle Detection of Shiga Toxins by Lateral Flow Assay
Toxins 2015, 7(4), 1163-1173; https://doi.org/10.3390/toxins7041163
Received: 4 March 2015 / Revised: 26 March 2015 / Accepted: 30 March 2015 / Published: 3 April 2015
Cited by 9 | PDF Full-text (697 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxin-producing Escherichia coli (STEC) produce shiga toxins (Stxs) that can cause human disease and death. The contamination of food products with STEC represents a food safety problem that necessitates rapid and effective detection strategies to mitigate risk. In this manuscript, we report [...] Read more.
Shiga toxin-producing Escherichia coli (STEC) produce shiga toxins (Stxs) that can cause human disease and death. The contamination of food products with STEC represents a food safety problem that necessitates rapid and effective detection strategies to mitigate risk. In this manuscript, we report the development of a colorimetric lateral flow assay (LFA) for the rapid detection of Stxs in <10 min using a pair of monoclonal antibodies that bind epitopes common to Stx1 and six Stx2 variants. This LFA provides a rapid and sensitive test for the detection of Stxs directly from STEC culture supernatants or at risk food samples with a 0.1 ng/mL limit of detection (LOD) for Stx2a. This Stx LFA is applicable for use in the rapid evaluation of Stx production from cultured E. coli strains or as a tool to augment current methods as part of food safety testing. Full article
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2011

Jump to: 2018, 2017, 2016, 2015

Open AccessArticle Impact of the Nature and Size of the Polymeric Backbone on the Ability of Heterobifunctional Ligands to Mediate Shiga Toxin and Serum Amyloid P Component Ternary Complex Formation
Toxins 2011, 3(9), 1065-1088; https://doi.org/10.3390/toxins3091065
Received: 14 July 2011 / Revised: 16 August 2011 / Accepted: 19 August 2011 / Published: 25 August 2011
Cited by 9 | PDF Full-text (525 KB) | HTML Full-text | XML Full-text
Abstract
Inhibition of AB5-type bacterial toxins can be achieved by heterobifunctional ligands (BAITs) that mediate assembly of supramolecular complexes involving the toxin’s pentameric cell membrane-binding subunit and an endogenous protein, serum amyloid P component, of the innate immune system. Effective in vivo [...] Read more.
Inhibition of AB5-type bacterial toxins can be achieved by heterobifunctional ligands (BAITs) that mediate assembly of supramolecular complexes involving the toxin’s pentameric cell membrane-binding subunit and an endogenous protein, serum amyloid P component, of the innate immune system. Effective in vivo protection from Shiga toxin Type 1 (Stx1) is achieved by polymer-bound, heterobifunctional inhibitors-adaptors (PolyBAITs), which exhibit prolonged half-life in circulation and by mediating formation of face-to-face SAP-AB5 complexes, block receptor recognition sites and redirect toxins to the spleen and liver for degradation. Direct correlation between solid-phase activity and protective dose of PolyBAITs both in the cytotoxicity assay and in vivo indicate that the mechanism of protection from intoxication is inhibition of toxin binding to the host cell membrane. The polymeric scaffold influences the activity not only by clustering active binding fragments but also by sterically interfering with the supramolecular complex assembly. Thus, inhibitors based on N-(2-hydroxypropyl) methacrylamide (HPMA) show significantly lower activity than polyacrylamide-based analogs. The detrimental steric effect can partially be alleviated by extending the length of the spacer, which separates pendant ligand from the backbone, as well as extending the spacer, which spans the distance between binding moieties within each heterobifunctional ligand. Herein we report that polymer size and payload of the active ligand had moderate effects on the inhibitor’s activity. Full article
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Open AccessShort Note Loss of vtx Genes after the First Subcultivation Step of Verocytotoxigenic Escherichia coli O157 and Non-O157 during Isolation from Naturally Contaminated Fecal Samples
Toxins 2011, 3(6), 672-677; https://doi.org/10.3390/toxins3060672
Received: 12 April 2011 / Revised: 1 June 2011 / Accepted: 8 June 2011 / Published: 20 June 2011
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Abstract
Verocytotoxins VT1 and VT2, produced by Verocytotoxigenic Escherichia coli (VTEC), are encoded on temperate bacteriophages. Several studies reported the loss of the vtx genes after multiple subcultivation steps or long preservation. The objective of this study was to determine if the loss of [...] Read more.
Verocytotoxins VT1 and VT2, produced by Verocytotoxigenic Escherichia coli (VTEC), are encoded on temperate bacteriophages. Several studies reported the loss of the vtx genes after multiple subcultivation steps or long preservation. The objective of this study was to determine if the loss of the verocytotoxin genes can already occur during the first subcultivation step. Consequently, the stability of the vtx genes were tested in 40 isolates originating from 40 vtx-positive fecal samples after the first subcultivation step following the isolation procedure. The loss occurred in 12 out of 40 strains tested and was rather rare among the O157 strains compared to the non-O157 strains. This is the first study demonstrating that the loss of the verocytotoxin genes can already occur after the first subcultivation step. This may lead to an underestimation of VTEC positive samples. Full article
Open AccessBrief Report Detection of stx1 and stx2 Genes in Pennsylvanian White-Tailed Deer
Toxins 2011, 3(6), 640-646; https://doi.org/10.3390/toxins3060640
Received: 3 May 2011 / Revised: 10 June 2011 / Accepted: 14 June 2011 / Published: 16 June 2011
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Abstract
Shiga toxin-producing E. coli carrying the stx1 and/or stx2 genes can cause multi-symptomatic illness in humans. A variety of terrestrial and aquatic environmental reservoirs of stx have been described. Culture based detection of microbes in deer species have found a low [...] Read more.
Shiga toxin-producing E. coli carrying the stx1 and/or stx2 genes can cause multi-symptomatic illness in humans. A variety of terrestrial and aquatic environmental reservoirs of stx have been described. Culture based detection of microbes in deer species have found a low percentage of samples that have tested positive for Stx-producing microbes, suggesting that while deer may contain these microbes, their overall abundance in deer is low. In this study, quantitative PCR (qPCR) was utilized to test for the presence of stx genes in white-tailed deer fecal matter in western Pennsylvania. In this culture independent screening, nearly half of the samples tested positive for the stx2 gene, with a bias towards samples that were concentrated with stx2. This study, while limited in scope, suggests that deer may be a greater reservoir for stx than was previously thought. Full article
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Open AccessReview Shiga Toxin Interaction with Human Intestinal Epithelium
Toxins 2011, 3(6), 626-639; https://doi.org/10.3390/toxins3060626
Received: 20 April 2011 / Revised: 2 June 2011 / Accepted: 7 June 2011 / Published: 14 June 2011
Cited by 41 | PDF Full-text (257 KB) | HTML Full-text | XML Full-text
Abstract
After ingestion via contaminated food or water, enterohaemorrhagic E. coli colonises the intestinal mucosa and produces Shiga toxins (Stx). No Stx-specific secretion system has been described so far, and it is assumed that Stx are released into the gut lumen after bacterial lysis. [...] Read more.
After ingestion via contaminated food or water, enterohaemorrhagic E. coli colonises the intestinal mucosa and produces Shiga toxins (Stx). No Stx-specific secretion system has been described so far, and it is assumed that Stx are released into the gut lumen after bacterial lysis. Human intestinal epithelium does not express the Stx receptor Gb3 or other Stx binding sites, and it remains unknown how Stx cross the intestinal epithelial barrier and gain access to the systemic circulation. This review summarises current knowledge about the influence of the intestinal environment on Stx production and release, Stx interaction with intestinal epithelial cells and intracellular uptake, and toxin translocation into underlying tissues. Furthermore, it highlights gaps in understanding that need to be addressed by future research. Full article
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Open AccessReview Shiga Toxin: Expression, Distribution, and Its Role in the Environment
Toxins 2011, 3(6), 608-625; https://doi.org/10.3390/toxins3060608
Received: 3 May 2011 / Revised: 9 June 2011 / Accepted: 9 June 2011 / Published: 14 June 2011
Cited by 35 | PDF Full-text (336 KB) | HTML Full-text | XML Full-text
Abstract
In this review, we highlight recent work that has increased our understanding of the production and distribution of Shiga toxin in the environment. Specifically, we review studies that offer an expanded view of environmental reservoirs for Shiga toxin producing microbes in terrestrial and [...] Read more.
In this review, we highlight recent work that has increased our understanding of the production and distribution of Shiga toxin in the environment. Specifically, we review studies that offer an expanded view of environmental reservoirs for Shiga toxin producing microbes in terrestrial and aquatic ecosystems. We then relate the abundance of Shiga toxin in the environment to work that demonstrates that the genetic mechanisms underlying the production of Shiga toxin genes are modified and embellished beyond the classical microbial gene regulatory paradigms in a manner that apparently “fine tunes” the trigger to modulate the amount of toxin produced. Last, we highlight several recent studies examining microbe/protist interactions that postulate an answer to the outstanding question of why microbes might harbor and express Shiga toxin genes in the environment. Full article
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