Toxins

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Open AccessArticle

Overexpression of the Trichoderma brevicompactum tri5 Gene: Effect on the Expression of the Trichodermin Biosynthetic Genes and on Tomato Seedlings

by Anamariela Tijerino, Rosa Hermosa, Rosa E. Cardoza, Javier Moraga, Monica G. Malmierca, Josefina Aleu, Isidro G. Collado, Enrique Monte and Santiago Gutierrez

Toxins 2011, 3(9), 1220-1232; https://doi.org/10.3390/toxins3091220 - 23 Sep 2011

Cited by 40 | Viewed by 9257

Abstract

Trichoderma brevicompactum IBT 40841 produces trichodermin, a trichothecene-type toxin that shares most of the steps of its biosynthesis with harzianum A, another trichothecene produced by several Trichoderma species. The first specific step in the trichothecene biosynthesis is carried out by a terpene cylcase, [...] Read more.

Trichoderma brevicompactum IBT 40841 produces trichodermin, a trichothecene-type toxin that shares most of the steps of its biosynthesis with harzianum A, another trichothecene produced by several Trichoderma species. The first specific step in the trichothecene biosynthesis is carried out by a terpene cylcase, trichodiene synthase, that catalyzes the conversion of farnesyl pyrophosphate to trichodiene and that is encoded by the tri5 gene. Overexpression of tri5 resulted in increased levels of trichodermin production, but also in an increase in tyrosol and hydroxytyrosol production, two antioxidant compounds that may play a regulatory role in trichothecene biosynthesis, and also in a higher expression of three trichothecene genes, tri4, tri6 and tri10, and of the erg1 gene, which participates in the synthesis of triterpenes. The effect of tri5 overexpression on tomato seedling disease response was also studied. Full article

(This article belongs to the Special Issue Trichothecenes)

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Open AccessArticle

Role of Phospholipase A₂ in Retrograde Transport of Ricin

by Tove Irene Klokk, Anne Berit Dyve Lingelem, Anne-Grethe Myrann and Kirsten Sandvig

Toxins 2011, 3(9), 1203-1219; https://doi.org/10.3390/toxins3091203 - 23 Sep 2011

Cited by 5 | Viewed by 6782

Abstract

Ricin is a protein toxin classified as a bioterror agent, for which there are no known treatment options available after intoxication. It is composed of an enzymatically active A-chain connected by a disulfide bond to a cell binding B-chain. After internalization by endocytosis, [...] Read more.

Ricin is a protein toxin classified as a bioterror agent, for which there are no known treatment options available after intoxication. It is composed of an enzymatically active A-chain connected by a disulfide bond to a cell binding B-chain. After internalization by endocytosis, ricin is transported retrogradely to the Golgi and ER, from where the ricin A-chain is translocated to the cytosol where it inhibits protein synthesis and thus induces cell death. We have identified cytoplasmic phospholipase A₂ (PLA₂) as an important factor in ricin retrograde transport. Inhibition of PLA₂ protects against ricin challenge, however the toxin can still be endocytosed and transported to the Golgi. Interestingly, ricin transport from the Golgi to the ER is strongly impaired in response to PLA₂ inhibition. Confocal microscopy analysis shows that ricin is still colocalized with the trans-Golgi marker TGN46 in the presence of PLA₂ inhibitor, but less is colocalized with the cis-Golgi marker GM130. We propose that PLA₂ inhibition results in impaired ricin transport through the Golgi stack, thus preventing it from reaching the ER. Consequently, ricin cannot be translocated to the cytosol to exert its toxic action. Full article

(This article belongs to the Special Issue Ricin Toxin)

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Open AccessReview

The Potential Contributions of Lethal and Edema Toxins to the Pathogenesis of Anthrax Associated Shock

by Caitlin W. Hicks, Xizhong Cui, Daniel A. Sweeney, Yan Li, Amisha Barochia and Peter Q. Eichacker

Toxins 2011, 3(9), 1185-1202; https://doi.org/10.3390/toxins3091185 - 20 Sep 2011

Cited by 22 | Viewed by 8868

Abstract

Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 [...] Read more.

Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 outbreaks and the newly identified injectional drug use form of disease in the UK and Germany have been associated with relatively high mortality rates. One notable aspect of these cases has been the difficulty in supporting patients once shock has developed. Anthrax bacilli produce several different components which likely contribute to this shock. Growing evidence indicates that both major anthrax toxins may produce substantial cardiovascular dysfunction. Lethal toxin (LT) can alter peripheral vascular function; it also has direct myocardial depressant effects. Edema toxin (ET) may have even more pronounced peripheral vascular effects than LT, including the ability to interfere with the actions of conventional vasopressors. Additionally, ET also appears capable of interfering with renal sodium and water retention. Importantly, the two toxins exert their actions via quite different mechanisms and therefore have the potential to worsen shock and outcome in an additive fashion. Finally, both toxins have the ability to inhibit host defense and microbial clearance, possibly contributing to the very high bacterial loads noted in patients dying with anthrax. This last point is clinically relevant since emerging data has begun to implicate other bacterial components such as anthrax cell wall in the shock and organ injury observed with infection. Taken together, accumulating evidence regarding the potential contribution of LT and ET to anthrax-associated shock supports efforts to develop adjunctive therapies that target both toxins in patients with progressive shock. Full article

(This article belongs to the Special Issue Anthrax Toxin)

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Open AccessArticle

Passive and Active Vaccination Strategies to Prevent Ricin Poisoning

by Seth H. Pincus, Joan E. Smallshaw, Kejing Song, Jody Berry and Ellen S. Vitetta

Toxins 2011, 3(9), 1163-1184; https://doi.org/10.3390/toxins3091163 - 15 Sep 2011

Cited by 34 | Viewed by 10204

Abstract

Ricin toxin (RT) is derived from castor beans, produced by the plant Ricinus communis. RT and its toxic A chain (RTA) have been used therapeutically to arm ligands that target disease-causing cells. In most cases these ligands are cell-binding monoclonal antibodies (MAbs). [...] Read more.

Ricin toxin (RT) is derived from castor beans, produced by the plant Ricinus communis. RT and its toxic A chain (RTA) have been used therapeutically to arm ligands that target disease-causing cells. In most cases these ligands are cell-binding monoclonal antibodies (MAbs). These ligand-toxin conjugates or immunotoxins (ITs) have shown success in clinical trials [1]. Ricin is also of concern in biodefense and has been classified by the CDC as a Class B biothreat. Virtually all reports of RT poisoning have been due to ingestion of castor beans, since they grow abundantly throughout the world and are readily available. RT is easily purified and stable, and is not difficult to weaponize. RT must be considered during any “white powder” incident and there have been documented cases of its use in espionage [2,3]. The clinical syndrome resulting from ricin intoxication is dependent upon the route of exposure. Countermeasures to prevent ricin poisoning are being developed and their use will depend upon whether military or civilian populations are at risk of exposure. In this review we will discuss ricin toxin, its cellular mode of action, the clinical syndromes that occur following exposure and the development of pre- and post-exposure approaches to prevent of intoxication. Full article

(This article belongs to the Special Issue Ricin Toxin)

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Open AccessArticle

Modified Heat-Stable Toxins (hSTa) of Enterotoxigenic Escherichia coli Lose Toxicity but Display Antigenicity after Being Genetically Fused to Heat-Labile Toxoid LT(R192G)

by Mei Liu, Chengxian Zhang, Kristy Mateo, James P. Nataro, Donald C. Robertson and Weiping Zhang

Toxins 2011, 3(9), 1146-1162; https://doi.org/10.3390/toxins3091146 - 15 Sep 2011

Cited by 17 | Viewed by 7109

Abstract

Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of diarrhea in humans and animals. Heat-stable (STa) and heat-labile (LT) enterotoxins produced by ETEC disrupt fluid homeostasis in host small intestinal epithelial cells and cause fluid and electrolyte hyper-secretion that leads to diarrhea. [...] Read more.

Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of diarrhea in humans and animals. Heat-stable (STa) and heat-labile (LT) enterotoxins produced by ETEC disrupt fluid homeostasis in host small intestinal epithelial cells and cause fluid and electrolyte hyper-secretion that leads to diarrhea. ETEC strains producing STa or LT are sufficiently virulent to cause diarrhea, therefore STa and LT antigens must be included in ETEC vaccines. However, potent toxicity and poor immunogenicity (of STa) prevent them from being directly applied as vaccine components. While LT toxoids, especially LT(R192G), being used in vaccine development, STa toxoids have not been included. A recent study (IAI, 78:316-325) demonstrated porcine-type STa toxoids [pSTa(P12F) and pSTa(A13Q)] elicited protective anti-STa antibodies after being fused to a porcine-type LT toxoid [pLT(R192G)]. In this study, we substituted the 8th, 9th, 16th, or the 17th amino acid of a human-type STa (hSTa) and generated 28 modified STa peptides. We tested each STa peptide for toxicity and structure integrity, and found nearly all modified STa proteins showed structure alteration and toxicity reduction. Based on structure similarity and toxic activity, three modified STa peptides: STa(E8A), STa(T16Q) and STa(G17S), were selected to construct LT₁₉₂-STa_-toxoid fusions. Constructed fusions were used to immunize mice, and immunized mice developed anti-STa antibodies. Results from this study provide useful information in developing toxoid vaccines against ETEC diarrhea. Full article

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Open AccessArticle

Role of the Mannose Receptor (CD206) in Innate Immunity to Ricin Toxin

by Emily Gage, Maria O. Hernandez, Joanne M. O’Hara, Elizabeth A. McCarthy and Nicholas J. Mantis

Toxins 2011, 3(9), 1131-1145; https://doi.org/10.3390/toxins3091131 - 9 Sep 2011

Cited by 25 | Viewed by 8728

Abstract

The entry of ricin toxin into macrophages and certain other cell types in the spleen and liver results in toxin-induced inflammation, tissue damage and organ failure. It has been proposed that uptake of ricin into macrophages is facilitated by the mannose receptor (MR; [...] Read more.

The entry of ricin toxin into macrophages and certain other cell types in the spleen and liver results in toxin-induced inflammation, tissue damage and organ failure. It has been proposed that uptake of ricin into macrophages is facilitated by the mannose receptor (MR; CD206), a C-type lectin known to recognize the oligosaccharide side chains on ricin’s A (RTA) and B (RTB) subunits. In this study, we confirmed that the MR does indeed promote ricin binding, uptake and killing of monocytes in vitro. To assess the role of MR in the pathogenesis of ricin in vivo, MR knockout (MR^−/−) mice were challenged with the equivalent of 2.5× or 5× LD₅₀ of ricin by intraperitoneal injection. We found that MR^−/− mice were significantly more susceptible to toxin-induced death than their age-matched, wild-type control counterparts. These data are consistent with a role for the MR in scavenging and degradation of ricin, not facilitating its uptake and toxicity in vivo. Full article

(This article belongs to the Special Issue Ricin Toxin)

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Open AccessArticle

Anthrax Lethal Toxin-Induced Gene Expression Changes in Mouse Lung

by Eric K. Dumas, Philip M. Cox, Charles O’Connor Fullenwider, Melissa Nguyen, Michael Centola, Mark Barton Frank, Igor Dozmorov, Judith A. James and A. Darise Farris

Toxins 2011, 3(9), 1111-1130; https://doi.org/10.3390/toxins3091111 - 7 Sep 2011

Cited by 6 | Viewed by 9723

Abstract

A major virulence factor of Bacillus anthracis is the anthrax Lethal Toxin (LeTx), a bipartite toxin composed of Protective Antigen and Lethal Factor. Systemic administration of LeTx to laboratory animals leads to death associated with vascular leakage and pulmonary edema. In this study, [...] Read more.

A major virulence factor of Bacillus anthracis is the anthrax Lethal Toxin (LeTx), a bipartite toxin composed of Protective Antigen and Lethal Factor. Systemic administration of LeTx to laboratory animals leads to death associated with vascular leakage and pulmonary edema. In this study, we investigated whether systemic exposure of mice to LeTx would induce gene expression changes associated with vascular/capillary leakage in lung tissue. We observed enhanced susceptibility of A/J mice to death by systemic LeTx administration compared to the C57BL/6 strain. LeTx-induced groups of both up- and down-regulated genes were observed in mouse lungs 6 h after systemic administration of wild type toxin compared to lungs of mice exposed to an inactive mutant form of the toxin. Lungs of the less susceptible C57BL/6 strain showed 80% fewer differentially expressed genes compared to lungs of the more sensitive A/J strain. Expression of genes known to regulate vascular permeability was modulated by LeTx in the lungs of the more susceptible A/J strain. Unexpectedly, the largest set of genes with altered expression was immune specific, characterized by the up-regulation of lymphoid genes and the down-regulation of myeloid genes. Transcripts encoding neutrophil chemoattractants, modulators of tumor regulation and angiogenesis were also differentially expressed in both mouse strains. These studies provide new directions for the investigation of vascular leakage and pulmonary edema induced by anthrax LeTx. Full article

(This article belongs to the Special Issue Anthrax Toxin)

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Open AccessReview

Chemical and Metabolic Aspects of Antimetabolite Toxins Produced by Pseudomonas syringae Pathovars

by Eva Arrebola, Francisco M. Cazorla, Alejandro Perez-García and Antonio de Vicente

Toxins 2011, 3(9), 1089-1110; https://doi.org/10.3390/toxins3091089 - 31 Aug 2011

Cited by 41 | Viewed by 11547

Abstract

Pseudomonas syringae is a phytopathogenic bacterium present in a wide variety of host plants where it causes diseases with economic impact. The symptoms produced by Pseudomonas syringae include chlorosis and necrosis of plant tissues, which are caused, in part, by antimetabolite toxins. This [...] Read more.

Pseudomonas syringae is a phytopathogenic bacterium present in a wide variety of host plants where it causes diseases with economic impact. The symptoms produced by Pseudomonas syringae include chlorosis and necrosis of plant tissues, which are caused, in part, by antimetabolite toxins. This category of toxins, which includes tabtoxin, phaseolotoxin and mangotoxin, is produced by different pathovars of Pseudomonas syringae. These toxins are small peptidic molecules that target enzymes of amino acids’ biosynthetic pathways, inhibiting their activity and interfering in the general nitrogen metabolism. A general overview of the toxins’ chemistry, biosynthesis, activity, virulence and potential applications will be reviewed in this work. Full article

(This article belongs to the Special Issue Phytotoxins: Chemistry, Bioactivity and Potential Practical Applications)

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525 KiB

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

by Pavel I. Kitov, Eugenia Paszkiewicz, Joanna M. Sadowska, Zhicheng Deng, Marya Ahmed, Ravin Narain, Thomas P. Griener, George L. Mulvey, Glen D. Armstrong and David R. Bundle

Toxins 2011, 3(9), 1065-1088; https://doi.org/10.3390/toxins3091065 - 25 Aug 2011

Cited by 13 | Viewed by 9334

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

(This article belongs to the Special Issue Shiga Toxin)

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Toxins, Volume 3, Issue 9 (September 2011) – 9 articles , Pages 1065-1232

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