Toxic Ricin Research Articles

Simultaneous analysis of depurinated nucleic acid stem-loop and free adenine for ricin toxicity assay by hydrophilic interaction liquid chromatography-high-resolution mass spectrometry (HILIC-HRMS).

A simple, accurate method for measuring ricin activity was developed by detecting depurinated nucleic acid stem-loops and adenine using a commercially available hydrophilic interaction liquid chromatography (HILIC) column and a quadrupole-Orbitrap tandem mass spectrometer. Ricin in beverages was isolated using magnetic beads conjugated with ricin B-chain antibodies, and then incubated with a 14 mer RNA or a 12 mer RNA/DNA chimera, in which adenosine at the depurination site of RNA was replaced by deoxyadenosine. The adenine and depurinated nucleic acids were separated by HILIC and both analytes were detected by high-resolution mass spectrometry. The depurinated RNA was detectable at concentrations as low as 100 pM (6.5 μg mL-1) in orange juice and coffee, and 10 pM (0.65 μg mL-1) in milk and sake after incubation with the RNA substrate for 4 h. Free adenine was detectable at 10 pM in all matrices, although free adenine was also detected in all blanks and could not be distinguished from the coffee and orange juice blanks at 10 pM. When using the chimera as the substrate, the depurinated chimera and adenine were detected up to concentrations of 10 pM as larger peaks. However, since the depurinated chimera and adenine were also detected in blanks, careful judgment was needed to determine whether they were active. Following the assay, the captured ricin could be analyzed by enzymatic digestion and nano liquid chromatography-high-resolution mass spectrometry. The ricin A chain-specific T7A peptide was detectable at 10 pM for sake and at 100 pM for milk, orange juice, and coffee. Using the present method, a toxicity assay and qualitative analysis of ricin were feasible with a 0.2 mL beverage sample.

A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning.

Ricin is a highly potent toxin that has been used in various attempts at bioterrorism worldwide. Although a vaccine for preventing ricin poisoning (RiVax™) is in clinical development, there are currently no commercially available prophylaxis or treatments for ricin intoxication. Numerous studies have highlighted the potential of passive immunotherapy using anti-ricin monoclonal antibodies (mAbs) and have shown promising results in preclinical models. In this article, we describe the neutralizing and protective efficacy of a new generation of high-affinity anti-ricin mAbs, which bind and neutralize very efficiently both ricin isoforms D and E in vitro through cytotoxicity cell assays. In vivo, protection assay revealed that one of these mAbs (RicE5) conferred over 90% survival in a murine model challenged intranasally with a 5 LD50 of ricin and treated by intravenous administration of the mAbs 6 h post-intoxication. Notably, a 35% survival rate was observed even when treatment was administered 24 h post-exposure. Moreover, all surviving mice exhibited long-term immunity to high ricin doses. These findings offer promising results for the clinical development of a therapeutic candidate against ricin intoxication and may also pave the way for novel vaccination strategies against ricin or other toxins.

Ricin intoxication by lethal dose of castor seeds ingestion: a case report

IntroductionRicin intoxication is a serious condition with symptoms ranging from mild gastroenteritis to fatal outcomes due to shock and multi-organ failure. Intoxication from the ingestion of castor seeds is uncommon. However, its diagnosis is crucial, particularly with a clear history of exposure to castor seeds, regardless of the route of exposure (enteral or parenteral). Prompt diagnosis is essential to monitor and manage the patient effectively and to prevent potentially fatal outcomes. We report a case where ingestion of castor seeds resulted in gastroenteritis severe enough to necessitate emergency medical care.Case reportWe present the case of a 47-year-old Belgian woman of Moroccan descent, previously healthy who was admitted to the emergency department with symptoms of colicky abdominal pain, diarrhea, and vomiting following the ingestion of six castor beans. The patient was diagnosed with ricin intoxication, admitted for observation, and received symptomatic treatment. She was discharged home after a complete recovery three days later.ConclusionOur report underscores the clinical manifestations, hemodynamic changes, laboratory findings, and treatment of intoxication due to castor seed ingestion. It contributes to the limited literature on castor seed poisoning in humans, with a specific focus on cases in Belgium. This report aims to raise awareness among clinicians about this condition and emphasizes the importance of a comprehensive history-taking to prevent misdiagnosis and malpractice.

Identification and Biological Evaluation of a Novel Small-Molecule Inhibitor of Ricin Toxin.

The plant-derived toxin ricin is classified as a type 2 ribosome-inactivating protein (RIP) and currently lacks effective clinical antidotes. The toxicity of ricin is mainly due to its ricin toxin A chain (RTA), which has become an important target for drug development. Previous studies have identified two essential binding pockets in the active site of RTA, but most existing inhibitors only target one of these pockets. In this study, we used computer-aided virtual screening to identify a compound called RSMI-29, which potentially interacts with both active pockets of RTA. We found that RSMI-29 can directly bind to RTA and effectively attenuate protein synthesis inhibition and rRNA depurination induced by RTA or ricin, thereby inhibiting their cytotoxic effects on cells in vitro. Moreover, RSMI-29 significantly reduced ricin-mediated damage to the liver, spleen, intestine, and lungs in mice, demonstrating its detoxification effect against ricin in vivo. RSMI-29 also exhibited excellent drug-like properties, featuring a typical structural moiety of known sulfonamides and barbiturates. These findings suggest that RSMI-29 is a novel small-molecule inhibitor that specifically targets ricin toxin A chain, providing a potential therapeutic option for ricin intoxication.

Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.

Ricin, a highly potent plant-derived toxin, is considered a potential bioterrorism weapon due to its pronounced toxicity, high availability, and ease of preparation. Acute damage following pulmonary ricinosis is characterized by local cytokine storm, massive neutrophil infiltration, and edema formation, resulting in respiratory insufficiency and death. A designated equine polyclonal antibody-based (antitoxin) treatment was developed in our laboratory and proved efficacious in alleviating lung injury and increasing survival rates. Although short-term pathogenesis was thoroughly characterized in antitoxin-treated mice, the long-term damage in surviving mice was never determined. In this study, long-term consequences of ricin intoxication were evaluated 30 days post-exposure in mice that survived antitoxin treatment. Significant pulmonary sequelae were demonstrated in surviving antitoxin-treated mice, as reflected by prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance. The presented data highlight, for the first time to our knowledge, the possibility of long-term damage development in mice that survived lethal-dose pulmonary exposure to ricin due to antitoxin treatment.

Autophagic Degradation Is Involved in Cell Protection against Ricin Toxin.

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.

Comparative Aspects of Ricin Toxicity by Inhalation.

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.

Intentional ricin intoxication: A case report and review of the literature

Background: Ricin is considered one of the most potent toxins worldwide. Several case reports of intentional ricin intoxication have been described. Symptoms are mainly gastro-intestinal and may lead to hypovolemia and organ failure.

Medical Countermeasures against Ricin Intoxication.

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.

Purified Immunoglobulin F(ab′)2 Protects Mice and Rhesus Monkeys against Lethal Ricin Intoxication

Objective: Ricin is a highly toxic ribosome-inactivating lectin derived from castor beans. To date, no antidote is available to treat ricin-poisoned patients, and the development of a safe and effective antidote is urgently needed. Methods: First, ricin was prepared and used to construct a mouse model and a rhesus monkey model of ricin intoxication. Second, pepsin-digested F(ab′)2 fragments of serum IgG from horses injected with Freund’s-adjuvanted purified ricin were prepared. Third, the protective efficacy was evaluated in mouse and rhesus monkey models of lethal ricin intoxication. Results: The purity quotient of the prepared ricin and F(ab′)2 fragments exceeded 90% and 85% in the mouse and monkey models, respectively. The LD50 of ricin in mice and rhesus monkeys was 2.7 and 9 μg/kg, respectively. A quantity of 6.25 and 1.85 mg/kg F(ab′)2 was sufficient to treat lethal ricin intoxication in the mice and rhesus monkeys, respectively. Finally, the effect of this therapeutic antibody on peripheral blood immune cells was examined by analysis of peripheral blood immune cells through single cell sequencing. The underlying mechanism was found to involve restraining neutrophil activation, proliferation, and differentiation. Conclusion: Purified F(ab′)2 fragments administered with needle-free devices fully protect mice and rhesus monkeys against lethal doses of ricin intoxication.

Ricin and Abrin as Possible Agents of Bioterror

Plant toxins – ricin and abrin, obtained in a purified form from the beans of the castor bean and Abrus precatorius respectively, are considered by Western experts as potential damaging agents of a biological nature. The purpose of this work is to consider the danger of using ricin and abrin as agents of biological terrorism, as well as to assess the existing approaches and means for identifying these toxins, treating the intoxication caused by them, as well as the level of development of vaccine preparations. Both toxins have a similar molecular structure and mechanism of action. They consist of two subunits – A and B, resistant to high temperatures and extreme pH values. The mechanism of their damaging action is based on irreversible inhibition of the process of protein synthesis. The LD 50 of ricin for humans, according to various sources, is 3 μg/kg for inhalation and intravenous intake, 22–25 μg/kg for enteral intake, and about 500 μg/kg for subcutaneous intake. Abrin is more toxic than ricin, with an LD 50 for humans ranging from 0.1 μg/kg to 1 μg/kg depending on the route of entry. In case of enteral poisoning with ricin and abrin, the victims develop symptoms of gastroenteritis within a few hours: nausea, vomiting and pain in the abdominal cavity and chest, diarrhea. Bleeding from various parts of the gastrointestinal tract may be present. In future, general intoxication symptoms (headache, weakness, fever) and symptoms of multiple organ damage (acute renal failure and acute liver failure) develop. In the terminal stage, symptoms of vascular shock and vascular collapse are expressed. Death usually occurs on the third day or later. Cases of the use of ricin and abrin for criminal and terrorist purposes are described in the article. The main approaches and modern means of indication, means of treating ricin and abrine intoxication, as well as the state of development of vaccine preparations are shown. The given data show that the danger of these toxins as damaging agents is underestimated in Russia. It is necessary to develop diagnostic test systems that allow early detection of intoxication with plant toxins in the affected and the toxins themselves on environmental objects, as well as specific means for the treatment and prevention of acute poisoning with ricin and abrin.

Characterization of Lung Injury following Abrin Pulmonary Intoxication in Mice: Comparison to Ricin Poisoning.

Abrin is a highly toxic protein obtained from the seeds of the rosary pea plant Abrus precatorius, and it is closely related to ricin in terms of its structure and chemical properties. Both toxins inhibit ribosomal function, halt protein synthesis and lead to cellular death. The major clinical manifestations following pulmonary exposure to these toxins consist of severe lung inflammation and consequent respiratory insufficiency. Despite the high similarity between abrin and ricin in terms of disease progression, the ability to protect mice against these toxins by postexposure antibody-mediated treatment differs significantly, with a markedly higher level of protection achieved against abrin intoxication. In this study, we conducted an in-depth comparison between the kinetics of in vivo abrin and ricin intoxication in a murine model. The data demonstrated differential binding of abrin and ricin to the parenchymal cells of the lungs. Accordingly, toxin-mediated injury to the nonhematopoietic compartment was shown to be markedly lower in the case of abrin intoxication. Thus, profiling of alveolar epithelial cells demonstrated that although toxin-induced damage was restricted to alveolar epithelial type II cells following abrin intoxication, as previously reported for ricin, it was less pronounced. Furthermore, unlike following ricin intoxication, no direct damage was detected in the lung endothelial cell population following abrin exposure. Reduced impairment of intercellular junction molecules following abrin intoxication was detected as well. In contrast, similar damage to the endothelial surface glycocalyx layer was observed for the two toxins. We assume that the reduced damage to the lung stroma, which maintains a higher level of tissue integrity following pulmonary exposure to abrin compared to ricin, contributes to the high efficiency of the anti-abrin antibody treatment at late time points after exposure.

RIPpore: A Novel Host-Derived Method for the Identification of Ricin Intoxication through Oxford Nanopore Direct RNA Sequencing.

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.

Modulation of Ricin Intoxication by the Autophagy Inhibitor EACC.

The compound EACC (ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate) was recently reported to inhibit fusion of autophagosomes with lysosomes in a reversible manner by inhibiting recruitment of syntaxin 17 to autophagosomes. We report here that this compound also provides a strong protection against the protein toxin ricin as well as against other plant toxins such as abrin and modeccin. The protection did not seem to be caused by inhibition of endocytosis and retrograde transport, but rather by inhibited release of the enzymatically active A-moiety to the cytosol. The TANK-binding kinase 1 (TBK1) has been reported to phosphorylate syntaxin 17 and be required for initiation of autophagy. The inhibitor of TBK1, MRT68601, induced in itself a strong sensitization to ricin, apparently by increasing transport to the Golgi apparatus. Importantly, MRT68601 increased Golgi transport of ricin even in the presence of EACC, but EACC was still able to inhibit intoxication, supporting the idea that EACC protects at a late step along the retrograde pathway. These results also indicate that phosphorylation of syntaxin 17 is not required for the protection observed.

Ricin and Abrin as Possible Agents of Bioterror

Plant toxins – ricin and abrin, obtained in a purified form from the beans of the castor bean and Abrus precatorius respectively, are considered by Western experts as potential damaging agents of a biological nature. The purpose of this work is to consider the danger of using ricin and abrin as agents of biological terrorism, as well as to assess the existing approaches and means for identifying these toxins, treating the intoxication caused by them, as well as the level of development of vaccine preparations. Both toxins have a similar molecular structure and mechanism of action. They consist of two subunits – A and B, resistant to high temperatures and extreme pH values. The mechanism of their damaging action is based on irreversible inhibition of the process of protein synthesis. The LD50 of ricin for humans, according to various sources, is 3 µg/kg for inhalation and intravenous intake, 22–25 µg/kg for enteral intake, and about 500 µg/kg for subcutaneous intake. Abrin is more toxic than ricin, with an LD50 for humans ranging from 0.1 µg/kg to 1 µg/kg depending on the route of entry. In case of enteral poisoning with ricin and abrin, the victims develop symptoms of gastroenteritis within a few hours: nausea, vomiting and pain in the abdominal cavity and chest, diarrhea. Bleeding from various parts of the gastrointestinal tract may be present. In future, general intoxication symptoms (headache, weakness, fever) and symptoms of multiple organ damage (acute renal failure and acute liver failure) develop. In the terminal stage, symptoms of vascular shock and vascular collapse are expressed. Death usually occurs on the third day or later. Cases of the use of ricin and abrin for criminal and terrorist purposes are described in the article. The main approaches and modern means of indication, means of treating ricin and abrine intoxication, as well as the state of development of vaccine preparations are shown. The given data show that the danger of these toxins as damaging agents is underestimated in Russia. It is necessary to develop diagnostic test systems that allow early detection of intoxication with plant toxins in the affected and the toxins themselves on environmental objects, as well as specific means for the treatment and prevention of acute poisoning with ricin and abrin.

Single-domain antibodies neutralize ricin toxin intracellularly by blocking access to ribosomal P-stalk proteins

During ricin intoxication in mammalian cells, ricin's enzymatic (RTA) and binding (RTB) subunits disassociate in the endoplasmic reticulum. RTA is then translocated into the cytoplasm where, by virtue of its ability to depurinate a conserved residue within the sarcin–ricin loop (SRL) of 28S rRNA, it functions as a ribosome-inactivating protein. It has been proposed that recruitment of RTA to the SRL is facilitated by ribosomal P-stalk proteins, whose C-terminal domains interact with a cavity on RTA normally masked by RTB; however, evidence that this interaction is critical for RTA activity within cells is lacking. Here, we characterized a collection of single-domain antibodies (VHHs) whose epitopes overlap with the P-stalk binding pocket on RTA. The crystal structures of three such VHHs (V9E1, V9F9, and V9B2) in complex with RTA revealed not only occlusion of the ribosomal P-stalk binding pocket but also structural mimicry of C-terminal domain peptides by complementarity-determining region 3. In vitro assays confirmed that these VHHs block RTA–P-stalk peptide interactions and protect ribosomes from depurination. Moreover, when expressed as “intrabodies,” these VHHs rendered cells resistant to ricin intoxication. One VHH (V9F6), whose epitope was structurally determined to be immediately adjacent to the P-stalk binding pocket, was unable to neutralize ricin within cells or protect ribosomes from RTA in vitro. These findings are consistent with the recruitment of RTA to the SRL by ribosomal P-stalk proteins as a requisite event in ricin-induced ribosome inactivation.

Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine.

Ricin toxin isolated from the castor bean (Ricinus communis) is one of the most potent and lethal molecules known. While the pathophysiology and clinical consequences of ricin poisoning by the parenteral route, i.e., intramuscular penetration, have been described recently in various animal models, the preceding mechanism underlying the clinical manifestations of systemic ricin poisoning has not been completely defined. Here, we show that following intramuscular administration, ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages. Increased levels of circulating VEGF and decreased expression of vascular VE-cadherin caused blood vessel impairment, thereby promoting hyperpermeability in various organs. Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication, indicating that the vascular glycocalyx of both mice and swine underwent extensive damage. Finally, by using side-stream dark field intravital microscopy imaging, we determined that ricin poisoning leads to microvasculature malfunctioning, as manifested by aberrant blood flow and a significant decrease in the number of diffused microvessels. These findings, which suggest that glycocalyx shedding and microcirculation dysfunction play a major role in the pathology of systemic ricin poisoning, may serve for the formulation of specifically tailored therapies for treating parenteral ricin intoxication.

Differential ER stress as a driver of cell fate following ricin toxin exposure.

Inhalation of trace amounts of ricin toxin, a plant‐derived ribosome‐inactivating protein, results in ablation of alveolar macrophages, widespread epithelial damage, and the onset of acute respiratory distress syndrome (ARDS). While ricin's receptors are ubiquitous, certain cell types are more sensitive to ricin‐induced cell death than others for reasons that remain unclear. For example, we demonstrate in side‐by‐side studies that macrophage‐like differentiated THP‐1 (dTHP‐1) cells are hyper‐sensitive to ricin, while lung epithelium‐derived A549 cells are relatively insensitive, even though both cell types experience similar degrees of translational inhibition and p38 MAPK activation in response to ricin. Using a variety of small molecule inhibitors, we provide evidence that ER stress contributes to ricin‐mediated cytotoxicity of dTHP‐1 cells, but not A549 cells. On the other hand, the insensitivity of A549 cells to ricin was overcome by the addition of (TNF)‐related apoptosis‐inducing ligand (TRAIL; CD253), a known stimulator of extrinsic programmed cell death. These results have implications for understanding the complex pathophysiology of ricin‐induced ARDS in that they demonstrate that intrinsic (e.g., ER stress) and extrinsic (e.g., TRAIL) factors may ultimately determine the fate of specific cell types following ricin intoxication.

E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide targets abrin and ricin toxicity: Hitting two toxins with one stone

The efficacy of small molecule inhibitors (SMIs) against the enzymatic activity of Shiga toxin prompted the evaluation of their efficacy on related toxins viz. ricin and abrin. Ricin, like Shiga toxin, is listed as a category B bioweapon and belongs to the type II family of ribosome inactivating proteins (RIPs). Abrin though structurally and functionally similar to ricin, is considerably more toxic. In the present study, 35 compounds were evaluated in A549 cells in in vitro assays, of which 5 offered protection against abrin and 2 against ricin, with IC50 values ranging between 30.5-1379 μM and 300-341 μM, respectively. These findings are substantiated by fluorescence based thermal shift assay. Moreover, the binding of the promising compounds to the toxin components has been validated by Surface Plasmon Resonance assay and in vitro protein synthesis assay. In vivo studies reveal complete protection of mice with compound 4 E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide against orally administered lethal doses of, both, abrin and ricin. The present study thus proposes the emergence of E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide as a lead compound against RIPs.

Molecular aspects of creating vaccines for the prevention of poisoning ribosome-inactivating proteins of plant origin: current situation, problems of vaccine development

This article reviews the current understanding of the mechanism of action of the toxin, the clinical effects of ricin and abrin intoxication and how these relate to current and continuing prospects for vaccine development. The threat of bioterrorism worldwide has accelerated the demand for the development of therapies and vaccines against the ribosome-inactivating proteins. The diverse and unique nature of these toxins poses a challenge to vaccinologists. This paper will review the mechanism of toxicity and vaccines development to protect against the highly toxic plant-derived ribosomal toxins. Vaccine development is further complicated by the fact that as bioterrorism agents, abrin and ricin would most likely be disseminated as aerosols supplies. Our understanding of the mechanisms by which these toxins cross mucosal surfaces, and importance of mucosal immunity in preventing toxin uptake is only rudimentary. Research is now aimed at developing recombinant, attenuated vaccines based on a detailed understanding of the molecular mechanisms by which these toxins function. The evolution of the development of specific immunoprophylaxis of acute ricin poisoning from native toxoid to genetically engineered subunit vaccines based on the method of targeted mutagenesis is traced. The past several years have seen major advances in the development of a safe and efficacious ricin toxin vaccine. These vaccines are discussed in the context of the toxicity and structure of ricin. In this review we summarize ongoing efforts to leverage recent advances in the design and use of vaccines.