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Special Issue "Ricin Toxin"

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

Deadline for manuscript submissions: closed (31 July 2011)

Special Issue Editors

Guest Editor
Prof. Dr. Bruce Magun

Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239, USA
Website | E-Mail
Fax: +1 503 494 4253
Guest Editor
Prof. Dr. Jon D. Robertus

Department of Chemistry and Biochemistry, 1 University Station A5300, University of Texas, Austin, TX 78712, USA
Website | E-Mail
Phone: 512-471-3175

Special Issue Information

Dear Colleagues,

The toxicity of castor plant seeds has been known since antiquity; today we are aware that the toxic agent is a heterodimeric protein toxin called ricin. The exquisite potency of this protein has been of great interest to the general public. Ricin was used by the KGB to assassinate the dissident Georgi Markov in the famous “umbrella tip” incident; this story has featured in many news stories, documentaries, and several fictional adaptations. The scientific community shares this fascination with ricin. What is the secret behind its unusual potency, what biology can we learn from its analysis, can we use ricin as a tool for our benefit? Scientific investigation of ricin encompasses many sub disciplines. These include structural and mechanistic investigations of an enzyme that has evolved to catalytic perfection in its depurination of host ribosomes. The toxin subverts cell uptake and internal trafficking mechanisms to reach the cytoplasm and its investigation has shed light on those fields of research. Because of its ease of purification and toxicity, ricin has been implicated as a terrorist weapon. This has led to work on vaccines and chemical antidotes. There has also been interest in harnessing ricin to generate target specific toxins, particularly against tumor lines. Ricin has also stimulated basic research to understand the exact nature of its induction of morbidity and mortality. In this issue of Toxins we present contemporary work on this intriguing, multifaceted toxin.

Prof. Dr. Bruce Magun
Prof. Dr. Jon D. Robertus
Guest Editors

Keywords

  • ricin
  • drug design
  • cell trafficking
  • bioterrorism

Published Papers (11 papers)

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Research

Jump to: Review

Open AccessArticle Llama-Derived Single Domain Antibodies Specific for Abrus Agglutinin
Toxins 2011, 3(11), 1405-1419; doi:10.3390/toxins3111405
Received: 2 September 2011 / Revised: 23 October 2011 / Accepted: 1 November 2011 / Published: 11 November 2011
Cited by 11 | PDF Full-text (490 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Llama derived single domain antibodies (sdAb), the recombinantly expressed variable heavy domains from the unique heavy-chain only antibodies of camelids, were isolated from a library derived from llamas immunized with a commercial abrin toxoid preparation. Abrin is a potent toxin similar to ricin
[...] Read more.
Llama derived single domain antibodies (sdAb), the recombinantly expressed variable heavy domains from the unique heavy-chain only antibodies of camelids, were isolated from a library derived from llamas immunized with a commercial abrin toxoid preparation. Abrin is a potent toxin similar to ricin in structure, sequence and mechanism of action. The selected sdAb were evaluated for their ability to bind to commercial abrin as well as abrax (a recombinant abrin A-chain), purified abrin fractions, Abrus agglutinin (a protein related to abrin but with lower toxicity), ricin, and unrelated proteins. Isolated sdAb were also evaluated for their ability to refold after heat denaturation and ability to be used in sandwich assays as both capture and reporter elements. The best binders were specific for the Abrus agglutinin, showing minimal binding to purified abrin fractions or unrelated proteins. These binders had sub nM affinities and regained most of their secondary structure after heating to 95 °C. They functioned well in sandwich assays. Through gel analysis and the behavior of anti-abrin monoclonal antibodies, we determined that the commercial toxoid preparation used for the original immunizations contained a high percentage of Abrus agglutinin, explaining the selection of Abrus agglutinin binders. Used in conjunction with anti-abrin monoclonal and polyclonal antibodies, these reagents can fill a role to discriminate between the highly toxic abrin and the related, but much less toxic, Abrus agglutinin and distinguish between different crude preparations. Full article
(This article belongs to the Special Issue Ricin Toxin)
Open AccessArticle Role of Phospholipase A2 in Retrograde Transport of Ricin
Toxins 2011, 3(9), 1203-1219; doi:10.3390/toxins3091203
Received: 1 July 2011 / Revised: 25 August 2011 / Accepted: 16 September 2011 / Published: 23 September 2011
Cited by 3 | PDF Full-text (1972 KB) | HTML Full-text | XML Full-text | Supplementary Files
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)
Open AccessArticle Passive and Active Vaccination Strategies to Prevent Ricin Poisoning
Toxins 2011, 3(9), 1163-1184; doi:10.3390/toxins3091163
Received: 18 July 2011 / Revised: 17 August 2011 / Accepted: 5 September 2011 / Published: 15 September 2011
Cited by 14 | PDF Full-text (804 KB) | HTML Full-text | XML Full-text
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)
Open AccessArticle Role of the Mannose Receptor (CD206) in Innate Immunity to Ricin Toxin
Toxins 2011, 3(9), 1131-1145; doi:10.3390/toxins3091131
Received: 27 July 2011 / Revised: 26 August 2011 / Accepted: 30 August 2011 / Published: 9 September 2011
Cited by 13 | PDF Full-text (426 KB) | HTML Full-text | XML Full-text
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)
Open AccessArticle Adapting Yeast as Model to Study Ricin Toxin A Uptake and Trafficking
Toxins 2011, 3(7), 834-847; doi:10.3390/toxins3070834
Received: 7 June 2011 / Revised: 7 June 2011 / Accepted: 28 June 2011 / Published: 5 July 2011
Cited by 3 | PDF Full-text (708 KB) | HTML Full-text | XML Full-text
Abstract
The plant A/B toxin ricin represents a heterodimeric glycoprotein belonging to the family of ribosome inactivating proteins, RIPs. Its toxicity towards eukaryotic cells results from the depurination of 28S rRNA due to the N-glycosidic activity of ricin toxin A chain, RTA. Since
[...] Read more.
The plant A/B toxin ricin represents a heterodimeric glycoprotein belonging to the family of ribosome inactivating proteins, RIPs. Its toxicity towards eukaryotic cells results from the depurination of 28S rRNA due to the N-glycosidic activity of ricin toxin A chain, RTA. Since the extention of RTA by a mammalian-specific endoplasmic reticulum (ER) retention signal (KDEL) significantly increases RTA in vivo toxicity against mammalian cells, we here analyzed the phenotypic effect of RTA carrying the yeast-specific ER retention motif HDEL. Interestingly, such a toxin (RTAHDEL) showed a similar cytotoxic effect on yeast as a corresponding RTAKDEL variant on HeLa cells. Furthermore, we established a powerful yeast bioassay for RTA in vivo uptake and trafficking which is based on the measurement of dissolved oxygen in toxin-treated spheroplast cultures of S. cerevisiae. We show that yeast spheroplasts are highly sensitive against external applied RTA and further demonstrate that its toxicity is greatly enhanced by replacing the C-terminal KDEL motif by HDEL. Based on the RTA resistant phenotype seen in yeast knock-out mutants defective in early steps of endocytosis (∆end3) and/or in RTA depurination activity on 28S rRNA (∆rpl12B) we feel that the yeast-based bioassay described in this study is a powerful tool to dissect intracellular A/B toxin transport from the plasma membrane through the endosomal compartment to the ER. Full article
(This article belongs to the Special Issue Ricin Toxin)
Open AccessArticle Ricin Trafficking in Plant and Mammalian Cells
Toxins 2011, 3(7), 787-801; doi:10.3390/toxins3070787
Received: 18 May 2011 / Revised: 21 June 2011 / Accepted: 23 June 2011 / Published: 30 June 2011
Cited by 30 | PDF Full-text (414 KB) | HTML Full-text | XML Full-text
Abstract
Ricin is a heterodimeric plant protein that is potently toxic to mammalian and many other eukaryotic cells. It is synthesized and stored in the endosperm cells of maturing Ricinus communis seeds (castor beans). The ricin family has two major members, both, lectins, collectively
[...] Read more.
Ricin is a heterodimeric plant protein that is potently toxic to mammalian and many other eukaryotic cells. It is synthesized and stored in the endosperm cells of maturing Ricinus communis seeds (castor beans). The ricin family has two major members, both, lectins, collectively known as Ricinus communis agglutinin ll (ricin) and Ricinus communis agglutinin l (RCA). These proteins are stored in vacuoles within the endosperm cells of mature Ricinus seeds and they are rapidly broken down by hydrolysis during the early stages of post-germinative growth. Both ricin and RCA traffic within the plant cell from their site of synthesis to the storage vacuoles, and when they intoxicate mammalian cells they traffic from outside the cell to their site of action. In this review we will consider both of these trafficking routes. Full article
(This article belongs to the Special Issue Ricin Toxin)
Open AccessArticle Detection of Ricin Contamination in Ground Beef by Electrochemiluminescence Immunosorbent Assay
Toxins 2011, 3(4), 398-408; doi:10.3390/toxins3040398
Received: 16 March 2011 / Revised: 31 March 2011 / Accepted: 31 March 2011 / Published: 4 April 2011
Cited by 18 | PDF Full-text (183 KB) | HTML Full-text | XML Full-text
Abstract
Ricin is a highly toxic protein present in the seeds of Ricinus communis (castor), grown principally as a source of high quality industrial lubricant and as an ornamental. Because ricin has been used for intentional poisoning in the past and could be used
[...] Read more.
Ricin is a highly toxic protein present in the seeds of Ricinus communis (castor), grown principally as a source of high quality industrial lubricant and as an ornamental. Because ricin has been used for intentional poisoning in the past and could be used to contaminate food, there is a need for analytical methodology to detect ricin in food matrices. A monoclonal antibody-based method was developed for detecting and quantifying ricin in ground beef, a complex, fatty matrix. The limit of detection was 0.5 ng/g for the electrochemiluminescence (ECL) method and 1.5 ng/g for enzyme-linked immunosorbent assay (ELISA). The detection of nanogram per gram quantities of ricin spiked into retail samples of ground beef provides approximately 10,000-fold greater sensitivity than required to detect a toxic dose of ricin (>1 mg) in a 100 g sample. Full article
(This article belongs to the Special Issue Ricin Toxin)

Review

Jump to: Research

Open AccessReview Inhibitors of the Cellular Trafficking of Ricin
Toxins 2012, 4(1), 15-27; doi:10.3390/toxins4010015
Received: 23 November 2011 / Revised: 22 December 2011 / Accepted: 23 December 2011 / Published: 6 January 2012
Cited by 15 | PDF Full-text (656 KB) | HTML Full-text | XML Full-text
Abstract
Throughout the last decade, efforts to identify and develop effective inhibitors of the ricin toxin have focused on targeting its N-glycosidase activity. Alternatively, molecules disrupting intracellular trafficking have been shown to block ricin toxicity. Several research teams have recently developed high-throughput phenotypic
[...] Read more.
Throughout the last decade, efforts to identify and develop effective inhibitors of the ricin toxin have focused on targeting its N-glycosidase activity. Alternatively, molecules disrupting intracellular trafficking have been shown to block ricin toxicity. Several research teams have recently developed high-throughput phenotypic screens for small molecules acting on the intracellular targets required for entry of ricin into cells. These screens have identified inhibitory compounds that can protect cells, and sometimes even animals against ricin. We review these newly discovered cellular inhibitors of ricin intoxication, discuss the advantages and drawbacks of chemical-genetics approaches, and address the issues to be resolved so that the therapeutic development of these small-molecule compounds can progress. Full article
(This article belongs to the Special Issue Ricin Toxin)
Open AccessReview Understanding Ricin from a Defensive Viewpoint
Toxins 2011, 3(11), 1373-1392; doi:10.3390/toxins3111373
Received: 12 August 2011 / Revised: 13 October 2011 / Accepted: 14 October 2011 / Published: 4 November 2011
Cited by 29 | PDF Full-text (219 KB) | HTML Full-text | XML Full-text
Abstract
The toxin ricin has long been understood to have potential for criminal activity and there has been concern that it might be used as a mass-scale weapon on a military basis for at least two decades. Currently, the focus has extended to encompass
[...] Read more.
The toxin ricin has long been understood to have potential for criminal activity and there has been concern that it might be used as a mass-scale weapon on a military basis for at least two decades. Currently, the focus has extended to encompass terrorist activities using ricin to disrupt every day activities on a smaller scale. Whichever scenario is considered, there are features in common which need to be understood; these include the knowledge of the toxicity from ricin poisoning by the likely routes, methods for the detection of ricin in relevant materials and approaches to making an early diagnosis of ricin poisoning, in order to take therapeutic steps to mitigate the toxicity. This article will review the current situation regarding each of these stages in our collective understanding of ricin and how to defend against its use by an aggressor. Full article
(This article belongs to the Special Issue Ricin Toxin)
Open AccessReview Ricinus communis Intoxications in Human and Veterinary Medicine—A Summary of Real Cases
Toxins 2011, 3(10), 1332-1372; doi:10.3390/toxins3101332
Received: 15 August 2011 / Revised: 26 September 2011 / Accepted: 30 September 2011 / Published: 24 October 2011
Cited by 47 | PDF Full-text (5690 KB) | HTML Full-text | XML Full-text
Abstract
Accidental and intended Ricinus communis intoxications in humans and animals have been known for centuries but the causative agent remained elusive until 1888 when Stillmark attributed the toxicity to the lectin ricin. Ricinus communis is grown worldwide on an industrial scale for the
[...] Read more.
Accidental and intended Ricinus communis intoxications in humans and animals have been known for centuries but the causative agent remained elusive until 1888 when Stillmark attributed the toxicity to the lectin ricin. Ricinus communis is grown worldwide on an industrial scale for the production of castor oil. As by-product in castor oil production ricin is mass produced above 1 million tons per year. On the basis of its availability, toxicity, ease of preparation and the current lack of medical countermeasures, ricin has gained attention as potential biological warfare agent. The seeds also contain the less toxic, but highly homologous Ricinus communis agglutinin and the alkaloid ricinine, and especially the latter can be used to track intoxications. After oil extraction and detoxification, the defatted press cake is used as organic fertilizer and as low-value feed. In this context there have been sporadic reports from different countries describing animal intoxications after uptake of obviously insufficiently detoxified fertilizer. Observations in Germany over several years, however, have led us to speculate that the detoxification process is not always performed thoroughly and controlled, calling for international regulations which clearly state a ricin threshold in fertilizer. In this review we summarize knowledge on intended and unintended poisoning with ricin or castor seeds both in humans and animals, with a particular emphasis on intoxications due to improperly detoxified castor bean meal and forensic analysis. Full article
(This article belongs to the Special Issue Ricin Toxin)
Open AccessReview Structure-Based Design of Ricin Inhibitors
Toxins 2011, 3(10), 1233-1248; doi:10.3390/toxins3101233
Received: 11 August 2011 / Revised: 21 September 2011 / Accepted: 26 September 2011 / Published: 13 October 2011
Cited by 8 | PDF Full-text (3329 KB) | HTML Full-text | XML Full-text
Abstract
Ricin is a potent cytotoxin easily purified in large quantities. It presents a significant public health concern due to its potential use as a bioterrorism agent. For this reason, extensive efforts have been underway to develop antidotes against this deadly poison. The catalytic
[...] Read more.
Ricin is a potent cytotoxin easily purified in large quantities. It presents a significant public health concern due to its potential use as a bioterrorism agent. For this reason, extensive efforts have been underway to develop antidotes against this deadly poison. The catalytic A subunit of the heterodimeric toxin has been biochemically and structurally well characterized, and is an attractive target for structure-based drug design. Aided by computer docking simulations, several ricin toxin A chain (RTA) inhibitors have been identified; the most promising leads belonging to the pterin family. Development of these lead compounds into potent drug candidates is a challenging prospect for numerous reasons, including poor solubility of pterins, the large and highly polar secondary binding pocket of RTA, as well as the enzyme’s near perfect catalytic efficiency and tight binding affinity for its natural substrate, the eukaryotic ribosome. To date, the most potent RTA inhibitors developed using this approach are only modest inhibitors with apparent IC50 values in the 10−4 M range, leaving significant room for improvement. This review highlights the variety of techniques routinely employed in structure-based drug design projects, as well as the challenges faced in the design of RTA inhibitors. Full article
(This article belongs to the Special Issue Ricin Toxin)

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