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Toxins
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Advances in Ricin Antitoxins: From Intoxication to Diagnosis and Treatment
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Advances in Ricin Antitoxins: From Intoxication to Diagnosis and Treatment

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

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 17292

Special Issue Editors

Prof. Dr. Graeme C. Clark

E-Mail Website
Guest Editor
Defence Science and Technology Laboratory, Porton Down SP4 0JQ, UK
Interests: biothreat agents; intoxication; medical countermeasures; detection and identification
Dr. Damien Chong

E-Mail Website
Guest Editor
Defence Science and Technology Group, Fishermans Bend, VIC 3207, Australia
Interests: biological toxins; intoxication; medical countermeasures; therapeutics; diagnostics

Special Issue Information

Dear Colleagues,

Ricin is a potent (type 2) ribosome-inactivating protein toxin produced in the seeds of the castor bean plant Ricinus communis. Accidental and/or intentional exposure to the toxin can have serious consequences for the health and the survival of both humans and animals. This is a consequence of the potency of the toxin along with the prevalence of castor beans in the environment (i.e., increasing the likelihood of exposure). The identification of ricin intoxication in a clinical setting remains very challenging and is further complicated by a delayed onset of symptoms. Additionally, there is a current lack of licensed medical interventions, with supportive therapy representing the main clinical option. Nevertheless, a number of new small molecule inhibitors rationally developed using structural-functional analysis and that affect the intracellular trafficking of the toxin are alternative approaches to the more traditional antibody-based molecules which have also recently demonstrated promise as candidate countermeasures for the treatment of ricin exposure in animal models.  

This Special Issue will focus on the steps being taken to develop emerging candidate therapies for treating ricin exposure. In addition, research that will improve the following will also be considered:

  1. The efficacy of candidate therapies including formulation;
  2. Earlier diagnosis of exposure to the toxin;
  3. The understanding of the toxin’s direct mechanism of action or the process of intoxication that will aid the development of next-generation medical countermeasures.

Prof. Dr. Graeme C. Clark
Dr. Damien Chong
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind 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.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ricinus communis
  • ricin
  • intoxication
  • diagnosis
  • medical countermeasures
  • biothreat

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Published Papers (6 papers)

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Research

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13 pages, 2874 KiB  
Article
Autophagic Degradation Is Involved in Cell Protection against Ricin Toxin
by Yu Wu, Clémence Taisne, Nassim Mahtal, Alison Forrester, Marion Lussignol, Jean-Christophe Cintrat, Audrey Esclatine, Daniel Gillet and Julien Barbier
Toxins 2023, 15(5), 304; https://doi.org/10.3390/toxins15050304 - 23 Apr 2023
Cited by 7 | Viewed by 1875
Abstract
Autophagy is a complex and highly regulated degradative process, which acts as a survival pathway in response to cellular stress, starvation and pathogen infection. Ricin toxin is a plant toxin produced by the castor bean and classified as a category B biothreat agent. [...] Read more.
Autophagy is a complex and highly regulated degradative process, which acts as a survival pathway in response to cellular stress, starvation and pathogen infection. Ricin toxin is a plant toxin produced by the castor bean and classified as a category B biothreat agent. Ricin toxin inhibits cellular protein synthesis by catalytically inactivating ribosomes, leading to cell death. Currently, there is no licensed treatment for patients exposed to ricin. Ricin-induced apoptosis has been extensively studied; however, whether its intoxication via protein synthesis inhibition affects autophagy is not yet resolved. In this work, we demonstrated that ricin intoxication is accompanied by its own autophagic degradation in mammalian cells. Autophagy deficiency, by knocking down ATG5, attenuates ricin degradation, thus aggravating ricin-induced cytotoxicity. Additionally, the autophagy inducer SMER28 (Small Molecule Enhancer 28) partially protects cells against ricin cytotoxicity, an effect not observed in autophagy-deficient cells. These results demonstrate that autophagic degradation acts as a survival response of cells against ricin intoxication. This suggests that stimulation of autophagic degradation may be a strategy to counteract ricin intoxication. Full article
(This article belongs to the Special Issue Advances in Ricin Antitoxins: From Intoxication to Diagnosis and Treatment)
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21 pages, 6359 KiB  
Article
Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression
by Seth H. Pincus, Alexi Kyro, Grace A. Maresh, Tami Peters, Jacob Kempa, Tamera K. Marcotte, Zhanguo Gao, Jianping Ye, Valérie Copié and Kejing Song
Toxins 2022, 14(12), 820; https://doi.org/10.3390/toxins14120820 - 23 Nov 2022
Cited by 1 | Viewed by 2391
Abstract
Ricin toxin is an agent of biodefense concern and we have been developing countermeasures for ricin threats. In doing so, we sought biomarkers of ricin toxicosis and found that in mice parenteral injection of ricin toxin causes profound hypoglycemia, in the absence of [...] Read more.
Ricin toxin is an agent of biodefense concern and we have been developing countermeasures for ricin threats. In doing so, we sought biomarkers of ricin toxicosis and found that in mice parenteral injection of ricin toxin causes profound hypoglycemia, in the absence of other clinical laboratory abnormalities. We now seek to identify the mechanisms underlying this hypoglycemia. Within the first hours following injection, while still normoglycemic, lymphopenia and pro-inflammatory cytokine secretion were observed, particularly tumor necrosis factor (TNF)-α. The cytokine response evolved over the next day into a complex storm of both pro- and anti-inflammatory cytokines. Evaluation of pancreatic function and histology demonstrated marked islet hypertrophy involving predominantly β-cells, but only mildly elevated levels of insulin secretion, and diminished hepatic insulin signaling. Drops in blood glucose were observed even after destruction of β-cells with streptozotocin. In the liver, we observed a rapid and persistent decrease in the expression of glucose-6-phosphatase (G6Pase) RNA and protein levels, accompanied by a drop in glucose-6-phosphate and increase in glycogen. TNF-α has previously been reported to suppress G6Pase expression. In humans, a genetic deficiency of G6Pase results in glycogen storage disease, type-I (GSD-1), a hallmark of which is potentially fatal hypoglycemia. Full article
(This article belongs to the Special Issue Advances in Ricin Antitoxins: From Intoxication to Diagnosis and Treatment)
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17 pages, 3488 KiB  
Article
Distinct Metabolic States Are Observed in Hypoglycemia Induced in Mice by Ricin Toxin or by Fasting
by Jacob Kempa, Galen O’Shea-Stone, Corinne E. Moss, Tami Peters, Tamera K. Marcotte, Brian Tripet, Brian Eilers, Brian Bothner, Valérie Copié and Seth H. Pincus
Toxins 2022, 14(12), 815; https://doi.org/10.3390/toxins14120815 - 22 Nov 2022
Cited by 1 | Viewed by 2464
Abstract
Hypoglycemia may be induced by a variety of physiologic and pathologic stimuli and can result in life-threatening consequences if untreated. However, hypoglycemia may also play a role in the purported health benefits of intermittent fasting and caloric restriction. Previously, we demonstrated that systemic [...] Read more.
Hypoglycemia may be induced by a variety of physiologic and pathologic stimuli and can result in life-threatening consequences if untreated. However, hypoglycemia may also play a role in the purported health benefits of intermittent fasting and caloric restriction. Previously, we demonstrated that systemic administration of ricin toxin induced fatal hypoglycemia in mice. Here, we examine the metabolic landscape of the hypoglycemic state induced in the liver of mice by two different stimuli: systemic ricin administration and fasting. Each stimulus produced the same decrease in blood glucose and weight loss. The polar metabolome was studied using 1H NMR, quantifying 59 specific metabolites, and untargeted LC-MS on approximately 5000 features. Results were analyzed by multivariate analyses, using both principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA), to identify global metabolic patterns, and by univariate analyses (ANOVA) to assess individual metabolites. The results demonstrated that while there were some similarities in the responses to the two stimuli including decreased glucose, ADP, and glutathione, they elicited distinct metabolic states. The metabolite showing the greatest difference was O-phosphocholine, elevated in ricin-treated animals and known to be affected by the pro-inflammatory cytokine TNF-α. Another difference was the alternative fuel source utilized, with fasting-induced hypoglycemia primarily ketotic, while the response to ricin-induced hypoglycemia involves protein and amino acid catabolism. Full article
(This article belongs to the Special Issue Advances in Ricin Antitoxins: From Intoxication to Diagnosis and Treatment)
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15 pages, 4453 KiB  
Article
RIPpore: A Novel Host-Derived Method for the Identification of Ricin Intoxication through Oxford Nanopore Direct RNA Sequencing
by Yan Ryan, Abbie Harrison, Hannah Trivett, Catherine Hartley, Jonathan David, Graeme C. Clark and Julian A. Hiscox
Toxins 2022, 14(7), 470; https://doi.org/10.3390/toxins14070470 - 9 Jul 2022
Cited by 1 | Viewed by 2364
Abstract
Ricin is a toxin which enters cells and depurinates an adenine base in the sarcin-ricin loop in the large ribosomal subunit, leading to the inhibition of protein translation and cell death. We postulated that this depurination event could be detected using Oxford Nanopore [...] Read more.
Ricin is a toxin which enters cells and depurinates an adenine base in the sarcin-ricin loop in the large ribosomal subunit, leading to the inhibition of protein translation and cell death. We postulated that this depurination event could be detected using Oxford Nanopore Technologies (ONT) direct RNA sequencing, detecting a change in charge in the ricin loop. In this study, A549 cells were exposed to ricin for 2–24 h in order to induce depurination. In addition, a novel software tool was developed termed RIPpore that could quantify the adenine modification of ribosomal RNA induced by ricin upon respiratory epithelial cells. We provided demonstrable evidence for the first time that this base change detected is specific to RIP activity using a neutralising antibody against ricin. We believe this represents the first detection of depurination in RNA achieved using ONT sequencers. Collectively, this work highlights the potential for ONT and direct RNA sequencing to detect and quantify depurination events caused by ribosome-inactivating proteins such as ricin. RIPpore could have utility in the evaluation of new treatments and/or in the diagnosis of exposure to ricin. Full article
(This article belongs to the Special Issue Advances in Ricin Antitoxins: From Intoxication to Diagnosis and Treatment)
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Review

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22 pages, 948 KiB  
Review
Comparative Aspects of Ricin Toxicity by Inhalation
by Alexander Stoll, Daniel P. Shenton, A. Christopher Green and Jane L. Holley
Toxins 2023, 15(4), 281; https://doi.org/10.3390/toxins15040281 - 13 Apr 2023
Cited by 4 | Viewed by 2579
Abstract
The pathogenesis of ricin toxicity following inhalation has been investigated in many animal models, including the non-human primate (predominantly the rhesus macaque), pig, rabbit and rodent. The toxicity and associated pathology described in animal models are broadly similar, but variation appears to exist. [...] Read more.
The pathogenesis of ricin toxicity following inhalation has been investigated in many animal models, including the non-human primate (predominantly the rhesus macaque), pig, rabbit and rodent. The toxicity and associated pathology described in animal models are broadly similar, but variation appears to exist. This paper reviews the published literature and some of our own unpublished data and describes some of the possible reasons for this variation. Methodological variation is evident, including method of exposure, breathing parameters during exposure, aerosol characteristics, sampling protocols, ricin cultivar, purity and challenge dose and study duration. The model species and strain used represent other significant sources of variation, including differences in macro- and microscopic anatomy, cell biology and function, and immunology. Chronic pathology of ricin toxicity by inhalation, associated with sublethal challenge or lethal challenge and treatment with medical countermeasures, has received less attention in the literature. Fibrosis may follow acute lung injury in survivors. There are advantages and disadvantages to the different models of pulmonary fibrosis. To understand their potential clinical significance, these factors need to be considered when choosing a model for chronic ricin toxicity by inhalation, including species and strain susceptibility to fibrosis, time it takes for fibrosis to develop, the nature of the fibrosis (e.g., self-limiting, progressive, persistent or resolving) and ensuring that the analysis truly represents fibrosis. Understanding the variables and comparative aspects of acute and chronic ricin toxicity by inhalation is important to enable meaningful comparison of results from different studies, and for the investigation of medical countermeasures. Full article
(This article belongs to the Special Issue Advances in Ricin Antitoxins: From Intoxication to Diagnosis and Treatment)
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18 pages, 378 KiB  
Review
Medical Countermeasures against Ricin Intoxication
by Christine Rasetti-Escargueil and Arnaud Avril
Toxins 2023, 15(2), 100; https://doi.org/10.3390/toxins15020100 - 20 Jan 2023
Cited by 10 | Viewed by 4203
Abstract
Ricin toxin is a disulfide-linked glycoprotein (AB toxin) comprising one enzymatic A chain (RTA) and one cell-binding B chain (RTB) contained in the castor bean, a Ricinus species. Ricin inhibits peptide chain elongation via disruption of the binding between elongation factors and ribosomes, [...] Read more.
Ricin toxin is a disulfide-linked glycoprotein (AB toxin) comprising one enzymatic A chain (RTA) and one cell-binding B chain (RTB) contained in the castor bean, a Ricinus species. Ricin inhibits peptide chain elongation via disruption of the binding between elongation factors and ribosomes, resulting in apoptosis, inflammation, oxidative stress, and DNA damage, in addition to the classically known rRNA damage. Ricin has been used in traditional medicine throughout the world since prehistoric times. Because ricin toxin is highly toxic and can be readily extracted from beans, it could be used as a bioweapon (CDC B-list). Due to its extreme lethality and potential use as a biological weapon, ricin toxin remains a global public health concern requiring specific countermeasures. Currently, no specific treatment for ricin intoxication is available. This review focuses on the drugs under development. In particular, some examples are reviewed to demonstrate the proof of concept of antibody-based therapy. Chemical inhibitors, small proteins, and vaccines can serve as alternatives to antibodies or may be used in combination with antibodies. Full article
(This article belongs to the Special Issue Advances in Ricin Antitoxins: From Intoxication to Diagnosis and Treatment)
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