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Special Issue "Novel Properties of Well-Characterized Toxins"

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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 August 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Vernon L. Tesh (Website)

Department of Microbial and Molecular Pathogenesis, Medical Research and Education Building, Room 3002, College of Medicine, Texas A&M University System Health Science Center, 8447 State Highway 47, Bryan, TX 77807, USA
Fax: +1 979 845 3479
Interests: shiga toxins; verotoxins; ribosome-inactivating proteins; intracellular signaling pathways activated by microbial toxins; ER stress response; regulation of cytokine expression; innate immune response to microbial toxins; microbial pathogenesis

Special Issue Information

Dear Colleagues,

Compounds expressed by microbes and plants originally described to possess toxic activities (e.g., cytotoxins, neurotoxins, enterotoxins, etc.) have proven to be remarkably multifunctional molecules. For example, the capacity of Shiga toxins, a family of cytotoxins expressed by enteric pathogens, to act as ribosome-inactivating proteins was characterized in the 1980’s. Yet, it has recently been shown that in addition to protein synthesis inhibition, Shiga toxins are capable of: i) mediating membrane curvature and invagination; ii) triggering protein kinase signaling cascades upon membrane receptor binding; iii) being routed to multiple intracellular compartments including lysosomes, the endoplasmic reticulum, and nuclear membranes; iv) mediating transcytotic transport across polarized epithelial monolayers without cytotoxicity; v) activating the ribotoxic stress response leading to MAPK activation; vi) activating the ER stress pathway leading to induction of transcription factors and chaperone expression; vii) inducing chemokine expression by human intestinal epithelial cells; viii) inducing cytokine expression by macrophages; ix) altering normal cell cycling; x) altering cytoskeletal elements; and xi) inducing apoptosis in some cell types and inhibiting spontaneous apoptosis in other cells. Thus, these “toxins” activate a myriad of biological processes, many of which may contribute to pathogenesis. The ability to genetically manipulate toxin genes to produce toxoids (mutations that attenuate toxicity) has revealed many heretofore uncharacterized biological properties of toxins. In this special issue of Toxins, we will explore recently described novel properties of well-characterized toxins, discuss their role in pathogenesis, and review potential clinical applications to prevent or ameliorate toxin-mediated disease.

Prof. Dr. Vernon L. Tesh
Guest Editor

 

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed Open Access monthly journal published by MDPI.

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Keywords

  • microbial toxins
  • plant toxins
  • biological functions of toxins
  • non-toxic properties of toxins
  • cellular response to toxins
  • pathogenesis

Published Papers (29 papers)

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Research

Jump to: Review, Other

Open AccessArticle Shiga Toxin Type 2dact Displays Increased Binding to Globotriaosylceramide in vitro and Increased Lethality in Mice after Activation by Elastase
Toxins 2013, 5(11), 2074-2092; doi:10.3390/toxins5112074
Received: 29 August 2013 / Revised: 31 October 2013 / Accepted: 4 November 2013 / Published: 8 November 2013
Cited by 3 | PDF Full-text (2220 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxin type 2dact (Stx2dact), an Stx2 variant originally identified from Escherichia coli O91:H21 strain B2F1, displays increased cytotoxicity after activation by elastase present in intestinal mucus. Activation is a result of cleavage of two amino acids from the C-terminal tail of [...] Read more.
Shiga toxin type 2dact (Stx2dact), an Stx2 variant originally identified from Escherichia coli O91:H21 strain B2F1, displays increased cytotoxicity after activation by elastase present in intestinal mucus. Activation is a result of cleavage of two amino acids from the C-terminal tail of the A2 subunit. In this study, we hypothesized that activation leads to increased binding of toxin to its receptor on host cells both in vitro and in vivo. To test this theory, Stx2dact was treated with elastase or buffer alone and then each toxin was assessed for binding to purified globotriaosylceramide (Gb3) in an enzyme-linked immunosorbent assay, or cells in culture by immunofluorescence, or flow cytometry. Elastase- and buffer-treated Stx2dact were also evaluated for binding to mouse kidney tissue and for relative lethality in mice. We found that activated Stx2dact had a greater capacity to bind purified Gb3, cells in culture, and mouse kidney tissue and was more toxic for mice than was non-activated Stx2dact. Thus, one possible mechanism for the augmented cytotoxicity of Stx2dact after activation is its increased capacity to bind target cells, which, in turn, may cause greater lethality of elastase-treated toxin for mice and enhanced virulence for humans of E. coli strains that express Stx2dact. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Short Toxin-like Proteins Attack the Defense Line of Innate Immunity
Toxins 2013, 5(7), 1314-1331; doi:10.3390/toxins5071314
Received: 15 May 2013 / Revised: 16 July 2013 / Accepted: 16 July 2013 / Published: 23 July 2013
Cited by 8 | PDF Full-text (2204 KB) | HTML Full-text | XML Full-text
Abstract
ClanTox (classifier of animal toxins) was developed for identifying toxin-like candidates from complete proteomes. Searching mammalian proteomes for short toxin-like proteins (coined TOLIPs) revealed a number of overlooked secreted short proteins with an abundance of cysteines throughout their sequences. We applied bioinformatics [...] Read more.
ClanTox (classifier of animal toxins) was developed for identifying toxin-like candidates from complete proteomes. Searching mammalian proteomes for short toxin-like proteins (coined TOLIPs) revealed a number of overlooked secreted short proteins with an abundance of cysteines throughout their sequences. We applied bioinformatics and data-mining methods to infer the function of several top predicted candidates. We focused on cysteine-rich peptides that adopt the fold of the three-finger proteins (TFPs). We identified a cluster of duplicated genes that share a structural similarity with elapid neurotoxins, such as α-bungarotoxin. In the murine proteome, there are about 60 such proteins that belong to the Ly6/uPAR family. These proteins are secreted or anchored to the cell membrane. Ly6/uPAR proteins are associated with a rich repertoire of functions, including binding to receptors and adhesion. Ly6/uPAR proteins modulate cell signaling in the context of brain functions and cells of the innate immune system. We postulate that TOLIPs, as modulators of cell signaling, may be associated with pathologies and cellular imbalance. We show that proteins of the Ly6/uPAR family are associated with cancer diagnosis and malfunction of the immune system. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Determinants of pH-Dependent Modulation of Translocation in Dermonecrotic G-Protein-Deamidating Toxins
Toxins 2013, 5(6), 1167-1179; doi:10.3390/toxins5061167
Received: 17 May 2013 / Revised: 28 May 2013 / Accepted: 4 June 2013 / Published: 14 June 2013
PDF Full-text (647 KB) | HTML Full-text | XML Full-text
Abstract
Cytotoxic necrotizing factors from E. coli (CNF1, CNF2) and Yersinia (CNFy) share N-terminal sequence similarity with Pasteurella multocida toxin (PMT). This common N-terminal region harbors the receptor-binding and translocation domains that mediate uptake and delivery of the C-terminal catalytic [...] Read more.
Cytotoxic necrotizing factors from E. coli (CNF1, CNF2) and Yersinia (CNFy) share N-terminal sequence similarity with Pasteurella multocida toxin (PMT). This common N-terminal region harbors the receptor-binding and translocation domains that mediate uptake and delivery of the C-terminal catalytic cargo domains into the host cytosol. Subtle variations in the N-terminal ~500 amino acids of CNFs and PMT could allow for selective recognition of cellular receptors and thus, selective target cell specificity. Through studies with cellular inhibitors, we have identified an additional novel function for this region in modulating responses of these toxin proteins to changes in pH during intoxication and delivery of the catalytic cargo domain into the cytosol. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Effects of Clostridium difficile Toxin A and B on Human T Lymphocyte Migration
Toxins 2013, 5(5), 926-938; doi:10.3390/toxins5050926
Received: 12 January 2013 / Revised: 27 March 2013 / Accepted: 23 April 2013 / Published: 3 May 2013
Cited by 4 | PDF Full-text (1621 KB) | HTML Full-text | XML Full-text
Abstract
Bacterial products such as toxins can interfere with a variety of cellular processes, leading to severe human diseases. Clostridium difficile toxins, TcdA and TcdB are the primary contributing factors to the pathogenesis of C. difficile-associated diseases (CDAD). While the mechanisms for [...] Read more.
Bacterial products such as toxins can interfere with a variety of cellular processes, leading to severe human diseases. Clostridium difficile toxins, TcdA and TcdB are the primary contributing factors to the pathogenesis of C. difficile-associated diseases (CDAD). While the mechanisms for TcdA and TcdB mediated cellular responses are complex, it has been shown that these toxins can alter chemotactic responses of neutrophils and intestinal epithelial cells leading to innate immune responses and tissue damages. The effects of C. difficile toxins on the migration and trafficking of other leukocyte subsets, such as T lymphocytes, are not clear and may have potential implications for adaptive immunity. We investigated here the direct and indirect effects of TcdA and TcdB on the migration of human blood T cells using conventional cell migration assays and microfluidic devices. It has been found that, although both toxins decrease T cell motility, only TcdA but not TcdB decreases T cell chemotaxis. Similar effects are observed in T cell migration toward the TcdA- or TcdB-treated human epithelial cells. Our study demonstrated the primary role of TcdA (compared to TcdB) in altering T cell migration and chemotaxis, suggesting possible implications for C. difficile toxin mediated adaptive immune responses in CDAD. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Figures

Open AccessArticle Effects of Ergot Alkaloids on Liver Function of Piglets as Evaluated by the 13C-Methacetin and 13C-α-Ketoisocaproic Acid Breath Test
Toxins 2013, 5(1), 139-161; doi:10.3390/toxins5010139
Received: 10 September 2012 / Revised: 12 December 2012 / Accepted: 20 December 2012 / Published: 15 January 2013
Cited by 3 | PDF Full-text (310 KB) | HTML Full-text | XML Full-text
Abstract
Ergot alkaloids (the sum of individual ergot alkaloids are termed as total alkaloids, TA) are produced by the fungus Claviceps purpurea, which infests cereal grains commonly used as feedstuffs. Ergot alkaloids potentially modulate microsomal and mitochondrial hepatic enzymes. Thus, the aim [...] Read more.
Ergot alkaloids (the sum of individual ergot alkaloids are termed as total alkaloids, TA) are produced by the fungus Claviceps purpurea, which infests cereal grains commonly used as feedstuffs. Ergot alkaloids potentially modulate microsomal and mitochondrial hepatic enzymes. Thus, the aim of the present experiment was to assess their effects on microsomal and mitochondrial liver function using the 13C-Methacetin (MC) and 13C-α-ketoisocaproic acid (KICA) breath test, respectively. Two ergot batches were mixed into piglet diets, resulting in 11 and 22 mg (Ergot 5-low and Ergot 5-high), 9 and 14 mg TA/kg (Ergot 15-low and Ergot 15-high) and compared to an ergot-free control group. Feed intake and live weight gain decreased significantly with the TA content (p < 0.001). Feeding the Ergot 5-high diet tended to decrease the 60-min-cumulative 13CO2 percentage of the dose recovery (cPDR60) by 26% and 28% in the MC and KICA breath test, respectively, compared to the control group (p = 0.065). Therefore, both microsomal and mitochondrial liver function was slightly affected by ergot alkaloids. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Difference in F-Actin Depolymerization Induced by Toxin B from the Clostridium difficile Strain VPI 10463 and Toxin B from the Variant Clostridium difficile Serotype F Strain 1470
Toxins 2013, 5(1), 106-119; doi:10.3390/toxins5010106
Received: 14 November 2012 / Revised: 14 December 2012 / Accepted: 28 December 2012 / Published: 11 January 2013
Cited by 6 | PDF Full-text (2810 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Clostridium difficile toxin A (TcdA) and toxin B (TcdB) are the causative agent of the C. difficile-associated diarrhea (CDAD) and its severe form, the pseudomembranous colitis (PMC). TcdB from the C. difficile strain VPI10463 mono-glucosylates (thereby inactivates) the small GTPases Rho, [...] Read more.
Clostridium difficile toxin A (TcdA) and toxin B (TcdB) are the causative agent of the C. difficile-associated diarrhea (CDAD) and its severe form, the pseudomembranous colitis (PMC). TcdB from the C. difficile strain VPI10463 mono-glucosylates (thereby inactivates) the small GTPases Rho, Rac, and Cdc42, while Toxin B from the variant C. difficile strain serotype F 1470 (TcdBF) specifically mono-glucosylates Rac but not Rho(A/B/C). TcdBF is related to lethal toxin from C. sordellii (TcsL) that glucosylates Rac1 but not Rho(A/B/C). In this study, the effects of Rho-inactivating toxins on the concentrations of cellular F-actin were investigated using the rhodamine-phalloidin-based F-actin ELISA. TcdB induces F-actin depolymerization comparable to the RhoA-inactivating exoenzyme C3 from C. limosum (C3-lim). In contrast, the Rac-glucosylating toxins TcdBF and TcsL did not cause F-actin depolymerization. These observations led to the conclusion that F-actin depolymerization depends on the toxin’s capability of glucosylating RhoA. Furthermore, the integrity of focal adhesions (FAs) was analyzed using paxillin and p21-activated kinase (PAK) as FA marker proteins. Paxillin dephosphorylation was observed upon treatment of cells with TcdB, TcdBF, or C3-lim. In conclusion, the Rho-inactivating toxins induce loss of cell shape by either F-actin depolymerization (upon RhoA inactivation) or the disassembly of FAs (upon Rac1 inactivation). Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Verotoxin A Subunit Protects Lymphocytes and T Cell Lines against X4 HIV Infection in Vitro
Toxins 2012, 4(12), 1517-1534; doi:10.3390/toxins4121517
Received: 22 October 2012 / Revised: 24 November 2012 / Accepted: 6 December 2012 / Published: 14 December 2012
Cited by 2 | PDF Full-text (683 KB) | HTML Full-text | XML Full-text
Abstract
Our previous genetic, pharmacological and analogue protection studies identified the glycosphingolipid, Gb3 (globotriaosylceramide, Pk blood group antigen) as a natural resistance factor for HIV infection. Gb3 is a B cell marker (CD77), but a fraction of activated peripheral blood [...] Read more.
Our previous genetic, pharmacological and analogue protection studies identified the glycosphingolipid, Gb3 (globotriaosylceramide, Pk blood group antigen) as a natural resistance factor for HIV infection. Gb3 is a B cell marker (CD77), but a fraction of activated peripheral blood mononuclear cells (PBMCs) can also express Gb3. Activated PBMCs predominantly comprise CD4+ T-cells, the primary HIV infection target. Gb3 is the sole receptor for Escherichia coli verotoxins (VTs, Shiga toxins). VT1 contains a ribosome inactivating A subunit (VT1A) non-covalently associated with five smaller receptor-binding B subunits. The effect of VT on PHA/IL2-activated PBMC HIV susceptibility was determined. Following VT1 (or VT2) PBMC treatment during IL2/PHA activation, the small Gb3+/CD4+ T-cell subset was eliminated but, surprisingly, remaining CD4+ T-cell HIV-1IIIB (and HIV-1Ba-L) susceptibility was significantly reduced. The Gb3-Jurkat T-cell line was similarly protected by brief VT exposure prior to HIV-1IIIB infection. The efficacy of the VT1A subunit alone confirmed receptor independent protection. VT1 showed no binding or obvious Jurkat cell/PBMC effect. Protective VT1 concentrations reduced PBMC (but not Jurkat cell) proliferation by 50%. This may relate to the mechanism of action since HIV replication requires primary T-cell proliferation. Microarray analysis of VT1A-treated PBMCs indicated up regulation of 30 genes. Three of the top four were histone genes, suggesting HIV protection via reduced gene activation. VT blocked HDAC inhibitor enhancement of HIV infection, consistent with a histone-mediated mechanism. We speculate that VT1A may provide a benign approach to reduction of (X4 or R5) HIV cell susceptibility. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Comparative Cellular Toxicity of Hydrophilic and Hydrophobic Microcystins on Caco-2 Cells
Toxins 2012, 4(11), 1008-1023; doi:10.3390/toxins4111008
Received: 16 August 2012 / Revised: 8 October 2012 / Accepted: 9 October 2012 / Published: 25 October 2012
Cited by 19 | PDF Full-text (315 KB) | HTML Full-text | XML Full-text
Abstract
Microcystins (MC), cyanobacterial peptide hepatotoxins, comprise more than 100 different variants. They are rather polar molecules but some variants contain hydrophobic amino acid residues in the highly variable parts of the molecule. In MC-LF and MC-LW, the more hydrophobic phenylalanine (F) and [...] Read more.
Microcystins (MC), cyanobacterial peptide hepatotoxins, comprise more than 100 different variants. They are rather polar molecules but some variants contain hydrophobic amino acid residues in the highly variable parts of the molecule. In MC-LF and MC-LW, the more hydrophobic phenylalanine (F) and tryptophan (W), respectively, have replaced arginine (R) in MC-LR. Depending on the structure, microcystins are expected to have different in vivo toxicity and bioavailability, but only a few studies have considered the toxic properties of the more hydrophobic variants. The present study shows that MC-LF and MC-LW have more pronounced cytotoxic effects on Caco-2 cells as compared to those of MC-LR. Treatment of Caco-2 cells with MC-LW and especially MC-LF showed clear apoptotic features including shrinkage and blebbing, and the cell–cell adhesion was lost. An obvious reduction of cell proliferation and viability, assessed as the activity of mitochondrial dehydrogenases, was observed with MC-LF, followed by MC-LW and MC-LR. Cytotoxicity was quantified by measuring lactate dehydrogenase leakage. The more hydrophobic MC-LW and MC-LF induced markedly enhanced lactate dehydrogenase leakage compared to controls and MC-LR, indicating that the plasma membrane was damaged. All of the three toxins examined inhibited protein phosphatase 1, with MC-LF and MC-LW to a weaker extent compared to MC-LR. The higher toxic potential of the more hydrophobic microcystins could not be explained by the biophysical experiments performed. Taken together, our data show that the more hydrophobic microcystin variants induce higher toxicity in Caco-2 cells. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
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Open AccessArticle Vixapatin (VP12), a C-Type Lectin-Protein from Vipera xantina palestinae Venom: Characterization as a Novel Anti-angiogenic Compound
Toxins 2012, 4(10), 862-877; doi:10.3390/toxins4100862
Received: 30 August 2012 / Revised: 29 September 2012 / Accepted: 8 October 2012 / Published: 18 October 2012
Cited by 9 | PDF Full-text (763 KB) | HTML Full-text | XML Full-text
Abstract
A C-type lectin-like protein (CTL), originally identified as VP12 and lately named Vixapatin, was isolated and characterized from Israeli viper Vipera xantina palestinae snake venom. This CTL was characterized as a selective α2β1 integrin inhibitor with anti-melanoma metastatic activity. The major aim [...] Read more.
A C-type lectin-like protein (CTL), originally identified as VP12 and lately named Vixapatin, was isolated and characterized from Israeli viper Vipera xantina palestinae snake venom. This CTL was characterized as a selective α2β1 integrin inhibitor with anti-melanoma metastatic activity. The major aim of the present study was to prove the possibility that this protein is also a potent novel anti-angiogenic compound. Using an adhesion assay, we demonstrated that Vixapatin selectively and potently inhibited the α2 mediated adhesion of K562 over-expressing cells, with IC50 of 3 nM. 3 nM Vixapatin blocked proliferation of human dermal microvascular endothelial cells (HDMEC); 25 nM inhibited collagen I induced migration of human fibrosarcoma HT-1080 cells; and 50 nM rat C6 glioma and human breast carcinoma MDA-MB-231 cells. 1 µM Vixapatin reduced HDMEC tube formation by 75% in a Matrigel assay. Furthermore, 1 µM Vixapatin decreased by 70% bFGF-induced physiological angiogenesis, and by 94% C6 glioma-induced pathological angiogenesis, in shell-less embryonic quail chorioallantoic membrane assay. Vixapatin’s ability to inhibit all steps of the angiogenesis process suggest that it is a novel pharmacological tool for studying α2β1 integrin mediated angiogenesis and a lead compound for the development of a novel anti-angiogenic/angiostatic/anti-cancer drug. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Gi/o Protein-Dependent and -Independent Actions of Pertussis Toxin (PTX)
Toxins 2011, 3(7), 884-899; doi:10.3390/toxins3070884
Received: 13 April 2011 / Revised: 14 June 2011 / Accepted: 16 June 2011 / Published: 15 July 2011
Cited by 24 | PDF Full-text (425 KB) | HTML Full-text | XML Full-text
Abstract
Pertussis toxin (PTX) is a typical A-B toxin. The A-protomer (S1 subunit) exhibits ADP-ribosyltransferase activity. The B-oligomer consists of four subunits (S2 to S5) and binds extracellular molecules that allow the toxin to enter the cells. The A-protomer ADP-ribosylates the α subunits [...] Read more.
Pertussis toxin (PTX) is a typical A-B toxin. The A-protomer (S1 subunit) exhibits ADP-ribosyltransferase activity. The B-oligomer consists of four subunits (S2 to S5) and binds extracellular molecules that allow the toxin to enter the cells. The A-protomer ADP-ribosylates the α subunits of heterotrimeric Gi/o proteins, resulting in the receptors being uncoupled from the Gi/o proteins. The B-oligomer binds proteins expressed on the cell surface, such as Toll-like receptor 4, and activates an intracellular signal transduction cascade. Thus, PTX modifies cellular responses by at least two different signaling pathways; ADP-ribosylation of the Gαi/o proteins by the A-protomer (Gi/o protein-dependent action) and the interaction of the B-oligomer with cell surface proteins (Gi/o protein-independent action). Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Inhibition of the Unfolded Protein Response by Ricin A-Chain Enhances Its Cytotoxicity in Mammalian Cells
Toxins 2011, 3(5), 453-468; doi:10.3390/toxins3050453
Received: 16 April 2011 / Revised: 26 April 2011 / Accepted: 28 April 2011 / Published: 10 May 2011
Cited by 6 | PDF Full-text (454 KB) | HTML Full-text | XML Full-text
Abstract
Ricin is a highly toxic type II ribosome-inactivating protein that has potential as a biochemical weapon and as the toxic component of immunotoxins. The unfolded protein response (UPR) is a survival response that helps cells to recover from endoplasmic reticulum (ER) stress. [...] Read more.
Ricin is a highly toxic type II ribosome-inactivating protein that has potential as a biochemical weapon and as the toxic component of immunotoxins. The unfolded protein response (UPR) is a survival response that helps cells to recover from endoplasmic reticulum (ER) stress. Failure to recover from ER stress leads to apoptosis. In yeast, ricin-A-chain (RTA), the enzymatic component of ricin, inhibits UPR. Our goals were to determine if RTA inhibits UPR in two epithelial cell lines and if this affects RTA cytotoxicity. RTA alone did not induce UPR. However, RTA inhibited both phosphorylation of inositol-requiring enzyme 1 (IRE1) and splicing of X-box binding protein1 mRNA by the UPR-inducing agent tunicamycin (Tm). The ability of dithiothreitol (DTT) to activate eukaryotic translation initiation factor 2 alpha (eIF2α), a component of the PERK pathway, was also inhibited by RTA. Treatment with RTA in combination with Tm or DTT inhibited protein synthesis more than either agent did alone in one cell line, while caspase cleavage was enhanced by the treatment combination in both cell lines. These data indicate that RTA is more cytotoxic when UPR is inhibited. This ability to inhibit UPR may enhance the potential of RTA as a therapeutic immunotoxin in solid tumors. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Distribution of Gb3 Immunoreactivity in the Mouse Central Nervous System
Toxins 2010, 2(8), 1997-2006; doi:10.3390/toxins2081997
Received: 25 June 2010 / Accepted: 1 August 2010 / Published: 4 August 2010
Cited by 4 | PDF Full-text (760 KB) | HTML Full-text | XML Full-text
Abstract
We have shown previously that neurons in the mouse spinal cord express Gb3. We show in this article that distribution of anti-Gb3-Ab reactivity occurs in many different types of neurons of different areas of the central nervous system [...] Read more.
We have shown previously that neurons in the mouse spinal cord express Gb3. We show in this article that distribution of anti-Gb3-Ab reactivity occurs in many different types of neurons of different areas of the central nervous system (CNS). The immunoreactive neurons are in olfactory bulbs, cerebral cortex, hippocampus, striatum, amygdala, thalamus, hypothalamus, cerebellum, and medulla oblongata. In several different circumventricular organs where vessels do not have the blood-brain-barrier (BBB) structure, anti-Gb3-Ab is not positive for vessel structures, while neurons at these regions are positive. Also, within the ventricular area, ependymal cells in the third ventricle express Gb3, as revealed by anti-Gb3-Ab staining and intensity analysis. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessArticle Ricin Toxin Activates the NALP3 Inflammasome
Toxins 2010, 2(6), 1500-1514; doi:10.3390/toxins2061500
Received: 20 April 2010 / Revised: 30 April 2010 / Accepted: 4 May 2010 / Published: 17 June 2010
Cited by 20 | PDF Full-text (353 KB) | HTML Full-text | XML Full-text
Abstract
Ricin exhibits well characterized ribotoxic actions that lead to the inhibition of protein synthesis and the phosphorylation of stress activated protein kinases (SAPKs). Proinflammatory effects of ricin are thought to be caused by upregulation of genes encoding proinflammatory transcripts as a result [...] Read more.
Ricin exhibits well characterized ribotoxic actions that lead to the inhibition of protein synthesis and the phosphorylation of stress activated protein kinases (SAPKs). Proinflammatory effects of ricin are thought to be caused by upregulation of genes encoding proinflammatory transcripts as a result of the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We reported previously that macrophages and interleukin-1β (IL-1β) signaling are required for murine host immune responses to ricin delivered to the lungs. Here we report that ricin-mediated IL-1β release from bone-marrow derived macrophages is dependent on the NALP3 inflammasome, a scaffolding complex that mediates pro-IL-1β cleavage to active IL-1β by caspase-1. Release of IL-1β from macrophages was suppressed by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and high extracellular K+, which are two agents known to inhibit NALP3/cryopyrin/CIAS1 inflammasome formation. By employing inhibitors of p38 MAPK and JNK, we demonstrated that ricin-mediated release of IL-1β was enhanced, rather than suppressed, by inhibition of SAPK phosphorylation. In contrast, proteasomal inhibitors bortezomib and MG-132 completely suppressed ricin-induced IL-1β release from macrophages. These data suggest that ricin-mediated translational inhibition itself, by fostering the disappearance of labile protein(s) that normally suppress inflammasome formation, may constitute the mechanism underlying IL-1-dependent inflammatory signaling by ricin. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)

Review

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Open AccessReview Signaling Cascades of Pasteurella multocida Toxin in Immune Evasion
Toxins 2013, 5(9), 1664-1681; doi:10.3390/toxins5091664
Received: 30 August 2013 / Revised: 17 September 2013 / Accepted: 17 September 2013 / Published: 24 September 2013
Cited by 4 | PDF Full-text (459 KB) | HTML Full-text | XML Full-text
Abstract
Pasteurella multocida toxin (PMT) is a protein toxin found in toxigenic strains of Pasteurella multocida. PMT is the causative agent for atrophic rhinitis in pigs, a disease characterized by loss of nasal turbinate bones due to an inhibition of osteoblast function [...] Read more.
Pasteurella multocida toxin (PMT) is a protein toxin found in toxigenic strains of Pasteurella multocida. PMT is the causative agent for atrophic rhinitis in pigs, a disease characterized by loss of nasal turbinate bones due to an inhibition of osteoblast function and an increase in osteoclast activity and numbers. Apart from this, PMT acts as a strong mitogen, protects from apoptosis and has an impact on the differentiation and function of immune cells. Many signaling pathways have been elucidated, however, the effect of these signaling cascades as a means to subvert the host’s immune system are just beginning to unravel. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview CD28: Direct and Critical Receptor for Superantigen Toxins
Toxins 2013, 5(9), 1531-1542; doi:10.3390/toxins5091531
Received: 5 August 2013 / Revised: 30 August 2013 / Accepted: 5 September 2013 / Published: 9 September 2013
Cited by 4 | PDF Full-text (1113 KB) | HTML Full-text | XML Full-text
Abstract
Every adaptive immune response requires costimulation through the B7/CD28 axis, with CD28 on T-cells functioning as principal costimulatory receptor. Staphylococcal and streptococcal superantigen toxins hyperstimulate the T-cell-mediated immune response by orders of magnitude, inducing a lethal cytokine storm. We show that to [...] Read more.
Every adaptive immune response requires costimulation through the B7/CD28 axis, with CD28 on T-cells functioning as principal costimulatory receptor. Staphylococcal and streptococcal superantigen toxins hyperstimulate the T-cell-mediated immune response by orders of magnitude, inducing a lethal cytokine storm. We show that to elicit an inflammatory cytokine storm and lethality, superantigens must bind directly to CD28. Blocking access of the superantigen to its CD28 receptor with peptides mimicking the contact domains in either toxin or CD28 suffices to protect mice effectively from lethal shock. Our finding that CD28 is a direct receptor of superantigen toxins broadens the scope of microbial pathogen recognition mechanisms. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Figures

Open AccessReview The Toxicological Impacts of the Fusarium Mycotoxin, Deoxynivalenol, in Poultry Flocks with Special Reference to Immunotoxicity
Toxins 2013, 5(5), 912-925; doi:10.3390/toxins5050912
Received: 18 February 2013 / Revised: 19 April 2013 / Accepted: 19 April 2013 / Published: 29 April 2013
Cited by 14 | PDF Full-text (216 KB) | HTML Full-text | XML Full-text
Abstract
Deoxynivalenol (DON) is a common Fusarium toxin in poultry feed. Chickens are more resistant to the adverse impacts of deoxynivalenol (DON) compared to other species. In general, the acute form of DON mycotoxicosis rarely occurs in poultry flocks under normal conditions. However, [...] Read more.
Deoxynivalenol (DON) is a common Fusarium toxin in poultry feed. Chickens are more resistant to the adverse impacts of deoxynivalenol (DON) compared to other species. In general, the acute form of DON mycotoxicosis rarely occurs in poultry flocks under normal conditions. However, if diets contain low levels of DON (less than 5 mg DON/kg diet), lower productivity, impaired immunity and higher susceptibility to infectious diseases can occur. The molecular mechanism of action of DON has not been completely understood. A significant influence of DON in chickens is the impairment of immunological functions. It was known that low doses of DON elevated the serum IgA levels and affected both cell-mediated and humoral immunity in animals. DON is shown to suppress the antibody response to infectious bronchitis vaccine (IBV) and to Newcastle disease virus (NDV) in broilers (10 mg DON/kg feed) and laying hens (3.5 to 14 mg of DON/kg feed), respectively. Moreover, DON (10 mg DON/kg feed) decreased tumor necrosis factor alpha (TNF-α) in the plasma of broilers. DON can severely affect the immune system and, due to its negative impact on performance and productivity, can eventually result in high economic losses to poultry producers. The present review highlights the impacts of DON intoxication on cell mediated immunity, humoral immunity, gut immunity, immune organs and pro-inflammatory cytokines in chickens. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Review of the Inhibition of Biological Activities of Food-Related Selected Toxins by Natural Compounds
Toxins 2013, 5(4), 743-775; doi:10.3390/toxins5040743
Received: 27 March 2013 / Revised: 5 April 2013 / Accepted: 16 April 2013 / Published: 23 April 2013
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Abstract
There is a need to develop food-compatible conditions to alter the structures of fungal, bacterial, and plant toxins, thus transforming toxins to nontoxic molecules. The term ‘chemical genetics’ has been used to describe this approach. This overview attempts to survey and consolidate [...] Read more.
There is a need to develop food-compatible conditions to alter the structures of fungal, bacterial, and plant toxins, thus transforming toxins to nontoxic molecules. The term ‘chemical genetics’ has been used to describe this approach. This overview attempts to survey and consolidate the widely scattered literature on the inhibition by natural compounds and plant extracts of the biological (toxicological) activity of the following food-related toxins: aflatoxin B1, fumonisins, and ochratoxin A produced by fungi; cholera toxin produced by Vibrio cholerae bacteria; Shiga toxins produced by E. coli bacteria; staphylococcal enterotoxins produced by Staphylococcus aureus bacteria; ricin produced by seeds of the castor plant Ricinus communis; and the glycoalkaloid α-chaconine synthesized in potato tubers and leaves. The reduction of biological activity has been achieved by one or more of the following approaches: inhibition of the release of the toxin into the environment, especially food; an alteration of the structural integrity of the toxin molecules; changes in the optimum microenvironment, especially pH, for toxin activity; and protection against adverse effects of the toxins in cells, animals, and humans (chemoprevention). The results show that food-compatible and safe compounds with anti-toxin properties can be used to reduce the toxic potential of these toxins. Practical applications and research needs are suggested that may further facilitate reducing the toxic burden of the diet. Researchers are challenged to (a) apply the available methods without adversely affecting the nutritional quality, safety, and sensory attributes of animal feed and human food and (b) educate food producers and processors and the public about available approaches to mitigating the undesirable effects of natural toxins that may present in the diet. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Prevalence, Biogenesis, and Functionality of the Serine Protease Autotransporter EspP
Toxins 2013, 5(1), 25-48; doi:10.3390/toxins5010025
Received: 25 October 2012 / Revised: 18 December 2012 / Accepted: 21 December 2012 / Published: 28 December 2012
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Abstract
Enterohemorrhagic E. coli (EHEC) causes severe diseases in humans worldwide. One of its virulence factors is EspP, which belongs to the serine protease autotransporters of Enterobacteriaceae (SPATE) family. In this review we recapitulate the current data on prevalence, biogenesis, structural properties [...] Read more.
Enterohemorrhagic E. coli (EHEC) causes severe diseases in humans worldwide. One of its virulence factors is EspP, which belongs to the serine protease autotransporters of Enterobacteriaceae (SPATE) family. In this review we recapitulate the current data on prevalence, biogenesis, structural properties and functionality. EspP has been used to investigate mechanistic details of autotransport, and recent studies indicate that this transport mechanism is not autonomous but rather dependent on additional factors. Currently, five subtypes have been identified (EspPα-EspPε), with EspPα being associated with highly virulent EHEC serotypes and isolates from patients with severe disease. EspPα has been shown to degrade major proteins of the complement cascade, namely C3 and C5 and probably interferes with hemostasis by cleavage of coagulation factor V. Furthermore, EspPα is believed to contribute to biofilm formation perhaps by polymerization to rope-like structures. Together with the proteolytic activity, EspPα might ameliorate host colonization and interfere with host response. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview PI3K/Akt/mTOR, a Pathway Less Recognized for Staphylococcal Superantigen-Induced Toxicity
Toxins 2012, 4(11), 1343-1366; doi:10.3390/toxins4111343
Received: 27 September 2012 / Revised: 12 November 2012 / Accepted: 13 November 2012 / Published: 15 November 2012
Cited by 5 | PDF Full-text (949 KB) | HTML Full-text | XML Full-text
Abstract
Immunostimulating staphylococcal enterotoxin B (SEB) and related superantigenic toxins cause diseases in humans and laboratory animals by activating cells of the immune system. These toxins bind directly to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and specific Vβ [...] Read more.
Immunostimulating staphylococcal enterotoxin B (SEB) and related superantigenic toxins cause diseases in humans and laboratory animals by activating cells of the immune system. These toxins bind directly to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and specific Vβ regions of T-cell receptors (TCR), resulting in hyperactivation of both T lymphocytes and monocytes/macrophages. Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines, especially tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 causing clinical symptoms of fever, hypotension, and shock. The well-explored signal transduction pathways for SEB-induced toxicity downstream from TCR/MHC ligation and interaction of cell surface co-stimulatory molecules include the mitogen-activated protein kinase cascades and cytokine receptor signaling, culminating in NFκB activation. Independently, IL-2, IFNγ, and chemokines from activated T cells signal via the phosphoinositide 3-kinase (PI3K), the serine/threonine kinases, Akt and mammalian target of rapamycin (mTOR) pathways. This article reviews the signaling molecules induced by superantigens in the activation of PI3K/Akt/mTOR pathways leading to staphylococcal superantigen-induced toxicity and updates potential therapeutics against superantigens. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Shiga Toxins and the Pathophysiology of Hemolytic Uremic Syndrome in Humans and Animals
Toxins 2012, 4(11), 1261-1287; doi:10.3390/toxins4111261
Received: 17 September 2012 / Revised: 1 November 2012 / Accepted: 2 November 2012 / Published: 8 November 2012
Cited by 29 | PDF Full-text (445 KB) | HTML Full-text | XML Full-text
Abstract
Food-borne diseases are estimated at 76 million illnesses and 5000 deaths every year in the United States with the greatest burden on young children, the elderly and immunocompromised populations. The impact of efficient food distribution systems and a truly global food supply [...] Read more.
Food-borne diseases are estimated at 76 million illnesses and 5000 deaths every year in the United States with the greatest burden on young children, the elderly and immunocompromised populations. The impact of efficient food distribution systems and a truly global food supply ensures that outbreaks, previously sporadic and contained locally, are far more widespread and emerging pathogens have far more frequent infection opportunities. Enterohemorrhagic E. coli is an emerging food- and water-borne pathogen family whose Shiga-like toxins induce painful hemorrhagic colitis with potentially lethal complications of hemolytic uremic syndrome (HUS). The clinical manifestations of Shiga toxin-induced HUS overlap with other related syndromes yet molecular mechanisms differ considerably. As discussed herein, understanding these differences and the novel properties of the toxins is imperative for clinical management decisions, design of appropriate animal models, and choices of adjunctive therapeutics. The emergence of new strains with rapidly aggressive virulence makes clinical and research initiatives in this field a high public health priority. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Scorpion Toxins Specific for Potassium (K+) Channels: A Historical Overview of Peptide Bioengineering
Toxins 2012, 4(11), 1082-1119; doi:10.3390/toxins4111082
Received: 14 September 2012 / Revised: 22 October 2012 / Accepted: 23 October 2012 / Published: 1 November 2012
Cited by 25 | PDF Full-text (673 KB) | HTML Full-text | XML Full-text
Abstract
Scorpion toxins have been central to the investigation and understanding of the physiological role of potassium (K+) channels and their expansive function in membrane biophysics. As highly specific probes, toxins have revealed a great deal about channel structure and the [...] Read more.
Scorpion toxins have been central to the investigation and understanding of the physiological role of potassium (K+) channels and their expansive function in membrane biophysics. As highly specific probes, toxins have revealed a great deal about channel structure and the correlation between mutations, altered regulation and a number of human pathologies. Radio- and fluorescently-labeled toxin isoforms have contributed to localization studies of channel subtypes in expressing cells, and have been further used in competitive displacement assays for the identification of additional novel ligands for use in research and medicine. Chimeric toxins have been designed from multiple peptide scaffolds to probe channel isoform specificity, while advanced epitope chimerization has aided in the development of novel molecular therapeutics. Peptide backbone cyclization has been utilized to enhance therapeutic efficiency by augmenting serum stability and toxin half-life in vivo as a number of K+-channel isoforms have been identified with essential roles in disease states ranging from HIV, T-cell mediated autoimmune disease and hypertension to various cardiac arrhythmias and Malaria. Bioengineered scorpion toxins have been monumental to the evolution of channel science, and are now serving as templates for the development of invaluable experimental molecular therapeutics. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Advances in Deoxynivalenol Toxicity Mechanisms: The Brain as a Target
Toxins 2012, 4(11), 1120-1138; doi:10.3390/toxins4111120
Received: 18 September 2012 / Revised: 18 October 2012 / Accepted: 19 October 2012 / Published: 1 November 2012
Cited by 15 | PDF Full-text (1826 KB) | HTML Full-text | XML Full-text
Abstract
Deoxynivalenol (DON), mainly produced by Fusarium fungi, and also commonly called vomitoxin, is a trichothecene mycotoxin. It is one of the most abundant trichothecenes which contaminate cereals consumed by farm animals and humans. The extent of cereal contamination is strongly associated with [...] Read more.
Deoxynivalenol (DON), mainly produced by Fusarium fungi, and also commonly called vomitoxin, is a trichothecene mycotoxin. It is one of the most abundant trichothecenes which contaminate cereals consumed by farm animals and humans. The extent of cereal contamination is strongly associated with rainfall and moisture at the time of flowering and with grain storage conditions. DON consumption may result in intoxication, the severity of which is dose-dependent and may lead to different symptoms including anorexia, vomiting, reduced weight gain, neuroendocrine changes, immunological effects, diarrhea, leukocytosis, hemorrhage or circulatory shock. During the last two decades, many studies have described DON toxicity using diverse animal species as a model. While the action of the toxin on peripheral organs and tissues is well documented, data illustrating its effect on the brain are significantly less abundant. Yet, DON is known to affect the central nervous system. Recent studies have provided new evidence and detail regarding the action of the toxin on the brain. The purpose of the present review is to summarize critical studies illustrating this central action of the toxin and to suggest research perspectives in this field. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview The Interactions of Human Neutrophils with Shiga Toxins and Related Plant Toxins: Danger or Safety?
Toxins 2012, 4(3), 157-190; doi:10.3390/toxins4030157
Received: 16 January 2012 / Revised: 11 February 2012 / Accepted: 19 February 2012 / Published: 1 March 2012
Cited by 8 | PDF Full-text (642 KB) | HTML Full-text | XML Full-text
Abstract
Shiga toxins and ricin are well characterized similar toxins belonging to quite different biological kingdoms. Plant and bacteria have evolved the ability to produce these powerful toxins in parallel, while humans have evolved a defense system that recognizes molecular patterns common to [...] Read more.
Shiga toxins and ricin are well characterized similar toxins belonging to quite different biological kingdoms. Plant and bacteria have evolved the ability to produce these powerful toxins in parallel, while humans have evolved a defense system that recognizes molecular patterns common to foreign molecules through specific receptors expressed on the surface of the main actors of innate immunity, namely monocytes and neutrophils. The interactions between these toxins and neutrophils have been widely described and have stimulated intense debate. This paper is aimed at reviewing the topic, focusing particularly on implications for the pathogenesis and diagnosis of hemolytic uremic syndrome. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Mucosal Injuries due to Ribosome-Inactivating Stress and the Compensatory Responses of the Intestinal Epithelial Barrier
Toxins 2011, 3(10), 1263-1277; doi:10.3390/toxins3101263
Received: 3 August 2011 / Revised: 10 October 2011 / Accepted: 12 October 2011 / Published: 20 October 2011
Cited by 2 | PDF Full-text (322 KB) | HTML Full-text | XML Full-text
Abstract
Ribosome-inactivating (ribotoxic) xenobiotics are capable of using cleavage and modification to damage 28S ribosomal RNA, which leads to translational arrest. The blockage of global protein synthesis predisposes rapidly dividing tissues, including gut epithelia, to damage from various pathogenic processes, including epithelial inflammation [...] Read more.
Ribosome-inactivating (ribotoxic) xenobiotics are capable of using cleavage and modification to damage 28S ribosomal RNA, which leads to translational arrest. The blockage of global protein synthesis predisposes rapidly dividing tissues, including gut epithelia, to damage from various pathogenic processes, including epithelial inflammation and carcinogenesis. In particular, mucosal exposure to ribotoxic stress triggers integrated processes that are important for barrier regulation and re-constitution to maintain gut homeostasis. In the present study, various experimental models of the mucosal barrier were evaluated for their response to acute and chronic exposure to ribotoxic agents. Specifically, this review focuses on the regulation of epithelial junctions, epithelial transporting systems, epithelial cytotoxicity, and compensatory responses to mucosal insults. The primary aim is to characterize the mechanisms associated with the intestinal epithelial responses induced by ribotoxic stress and to discuss the implications of ribotoxic stressors as chemical modulators of mucosa-associated diseases such as ulcerative colitis and epithelial cancers. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Emergence of Anthrax Edema Toxin as a Master Manipulator of Macrophage and B Cell Functions
Toxins 2010, 2(7), 1881-1897; doi:10.3390/toxins2071881
Received: 18 June 2010 / Revised: 6 July 2010 / Accepted: 12 July 2010 / Published: 19 July 2010
Cited by 5 | PDF Full-text (599 KB) | HTML Full-text | XML Full-text
Abstract
Anthrax edema toxin (ET), a powerful adenylyl cyclase, is an important virulence factor of Bacillus anthracis. Until recently, only a modest amount of research was performed to understand the role this toxin plays in the organism’s immune evasion strategy. A new [...] Read more.
Anthrax edema toxin (ET), a powerful adenylyl cyclase, is an important virulence factor of Bacillus anthracis. Until recently, only a modest amount of research was performed to understand the role this toxin plays in the organism’s immune evasion strategy. A new wave of studies have begun to elucidate the effects this toxin has on a variety of host cells. While efforts have been made to illuminate the effect ET has on cells of the adaptive immune system, such as T cells, the greatest focus has been on cells of the innate immune system, particularly the macrophage. Here we discuss the immunoevasive activities that ET exerts on macrophages, as well as new research on the effects of this toxin on B cells. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Shiga Toxins: Intracellular Trafficking to the ER Leading to Activation of Host Cell Stress Responses
Toxins 2010, 2(6), 1515-1535; doi:10.3390/toxins2061515
Received: 27 April 2010 / Revised: 18 May 2010 / Accepted: 1 June 2010 / Published: 17 June 2010
Cited by 10 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
Abstract
Despite efforts to improve hygenic conditions and regulate food and drinking water safety, the enteric pathogens, Shiga toxin-producing Escherichia coli (STEC) and Shigella dysenteriae serotype 1 remain major public health concerns due to widespread outbreaks and the severity of extra-intestinal diseases they [...] Read more.
Despite efforts to improve hygenic conditions and regulate food and drinking water safety, the enteric pathogens, Shiga toxin-producing Escherichia coli (STEC) and Shigella dysenteriae serotype 1 remain major public health concerns due to widespread outbreaks and the severity of extra-intestinal diseases they cause, including acute renal failure and central nervous system complications. Shiga toxins are the key virulence factors expressed by these pathogens mediating extra-intestinal disease. Delivery of the toxins to the endoplasmic reticulum (ER) results in host cell protein synthesis inhibition, activation of the ribotoxic stress response, the ER stress response, and in some cases, the induction of apoptosis. Intrinsic and/or extrinsic apoptosis inducing pathways are involved in executing cell death following intoxication. In this review we provide an overview of the current understanding Shiga toxin intracellular trafficking, host cellular responses to the toxin and ER stress-induced apoptosis with an emphasis on recent findings. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview The Glucocorticoid Receptor: A Revisited Target for Toxins
Toxins 2010, 2(6), 1357-1380; doi:10.3390/toxins2061357
Received: 15 May 2010 / Accepted: 7 June 2010 / Published: 9 June 2010
Cited by 7 | PDF Full-text (407 KB) | HTML Full-text | XML Full-text
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses [...] Read more.
The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)
Open AccessReview Deoxynivalenol-Induced Proinflammatory Gene Expression: Mechanisms and Pathological Sequelae
Toxins 2010, 2(6), 1300-1317; doi:10.3390/toxins2061300
Received: 14 May 2010 / Revised: 25 May 2010 / Accepted: 28 May 2010 / Published: 1 June 2010
Cited by 43 | PDF Full-text (383 KB) | HTML Full-text | XML Full-text
Abstract
The trichothecene mycotoxin deoxynivalenol (DON) is commonly encountered in human cereal foods throughout the world as a result of infestation of grains in the field and in storage by the fungus Fusarium. Significant questions remain regarding the risks posed to humans [...] Read more.
The trichothecene mycotoxin deoxynivalenol (DON) is commonly encountered in human cereal foods throughout the world as a result of infestation of grains in the field and in storage by the fungus Fusarium. Significant questions remain regarding the risks posed to humans from acute and chronic DON ingestion, and how to manage these risks without imperiling access to nutritionally important food commodities. Modulation of the innate immune system appears particularly critical to DON’s toxic effects. Specifically, DON induces activation of mitogen-activated protein kinases (MAPKs) in macrophages and monocytes, which mediate robust induction of proinflammatory gene expression—effects that can be recapitulated in intact animals. The initiating mechanisms for DON-induced ribotoxic stress response appear to involve the (1) activation of constitutive protein kinases on the damaged ribosome and (2) autophagy of the chaperone GRP78 with consequent activation of the ER stress response. Pathological sequelae resulting from chronic low dose exposure include anorexia, impaired weight gain, growth hormone dysregulation and aberrant IgA production whereas acute high dose exposure evokes gastroenteritis, emesis and a shock-like syndrome. Taken together, the capacity of DON to evoke ribotoxic stress in mononuclear phagocytes contributes significantly to its acute and chronic toxic effects in vivo. It is anticipated that these investigations will enable the identification of robust biomarkers of effect that will be applicable to epidemiological studies of the human health effects of this common mycotoxin. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)

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Open AccessCommentary Yessotoxin as a Tool to Study Induction of Multiple Cell Death Pathways
Toxins 2012, 4(7), 568-579; doi:10.3390/toxins4070568
Received: 14 May 2012 / Revised: 14 July 2012 / Accepted: 21 July 2012 / Published: 23 July 2012
Cited by 17 | PDF Full-text (609 KB) | HTML Full-text | XML Full-text
Abstract
This work proposes to use the marine algal toxin yessotoxin (YTX) to establish reference model experiments to explore medically valuable effects from induction of multiple cell death pathways. YTX is one of few toxins reported to make such induction. It is a [...] Read more.
This work proposes to use the marine algal toxin yessotoxin (YTX) to establish reference model experiments to explore medically valuable effects from induction of multiple cell death pathways. YTX is one of few toxins reported to make such induction. It is a small molecule compound which at low concentrations can induce apoptosis in primary cultures, many types of cells and cell lines. It can also induce a non-apoptotic form of programmed cell death in BC3H1 myoblast cell lines. The present contribution reviews arguments that this type of induction may have principal interest outside this particular example. One principal effect of medical interest may be that cancer cells will not so easily adapt to the synergistic effects from induction of more than one death pathway as compared to induction of only apoptosis. Full article
(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)

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