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Pathogenic Leptospira Evolved a Unique Gene Family Comprised of Ricin B-Like Lectin Domain-Containing Cytotoxins.

Leptospirosis is a globally important neglected zoonotic disease. Previous data suggest that a family of virulence-modifying (VM) proteins (PF07598) is a distinctive feature of group I pathogenic Leptospira that evolved as important virulence determinants. Here, we show that one such VM protein, LA3490 (also known as Q8F0K3), is expressed by Leptospira interrogans serovar Lai, as a secreted genotoxin that is potently cytotoxic to human cells. Structural homology searches using Phyre2 suggested that VM proteins are novel R-type lectins containing tandem N-terminal ricin B-chain-like β-trefoil d…

Design and evaluation of DNA aptamers with "stem-loop-chain" structures for spectrum neutralization of ricin and abrin.

Ricin and abrin are classified as Type II ribosome-inactivating proteins (RIPs) toxins, posing significant potential threats to public safety and in bioterrorism incidents. They exert catalytic N-glycosidase activity by specifically recognizing highly conserved structural domains within the α-sarcin/ricin loop (SRL) of ribosomal rRNA, consequently inhibiting protein synthesis and ultimately inducing cell death. Currently, no licensed drugs are available for Type II RIPs, making the development of antidotes with broad-spectrum activity highly imperative. In this study, we engineered a series of…

Pathophysiological profile of awake and anesthetized pigs following systemic exposure to the highly lethal ricin toxin.

Ricin, a plant-derived toxin originating from the seeds of Ricinus communis (castor bean plant), is one of the most lethal toxins known. To date, no in-depth study of systemic exposure to ricin in a standardized large animal model has been reported. This study details for the first time the pathophysiological hemodynamic profile following systemic/intramuscular exposure to the ricin toxin in a porcine model by comprehensive cardiorespiratory monitoring of awake and anesthetized pigs. Unlike respiratory exposure to ricin, which is characterized by the development of acute respiratory distress s…

How ricin and Shiga toxin reach the cytosol of target cells: retrotranslocation from the endoplasmic reticulum.

A number of protein toxins bind at the surface of mammalian cells and after endocytosis traffic to the endoplasmic reticulum, where the toxi … he post-dislocation folding that results in catalytic activity. We describe here the dislocation of ricin A chain and Shiga toxin A chain, but also consider cholera toxin which bears a superficial structural resemblance to Shiga toxin. Recent studies not only describe how these proteins breach the ER membrane, but also reveal aspects of a fundamental ce …

Shiga toxin 1 and ricin A chain bind to human polymorphonuclear leucocytes through a common receptor.

The main cause of acute renal failure in children is HUS (haemolytic uraemic syndrome), a consequence of intestinal infections with Escheric … n-specific and of little biological significance. In the present study, we show that the A chain of ricin, the well-known plant RIP (ribosome-inactivating protein), interacts with PMN (Kd=10⁻⁹ M; 2×10⁵ binding sites) competing for the same receptor that recognizes Stx, whereas diphtheria toxin and several agonists of TLRs (Toll-like receptors) or the ma …

Hepatoxicity of ricin, saporin or a saporin immunotoxin: xanthine oxidase activity in rat liver and blood serum.

Male Wistar rats each received an i.p injection of the ribosome-inactivating proteins ricin or saporin, or a Ber-H2 (anti-CD30)-saporin immunotoxin at a dose corresponding to three times the LD50 calculated for mice. Animals were killed 24, 48 or 72 h after treatment. Histological examination showed hepatic necrosis in all treated animals, although the sinusoidal lining was affected only in ricin-poisoned rats. The activities of xanthine dehydrogenase (D-form) and oxidase (O-form) were determined spectrophotometrically in liver and serum samples. In ricin-treated animals the liver enzyme was p…

Anti-B4-blocked ricin synergizes with doxorubicin and etoposide on multidrug-resistant and drug-sensitive tumors.

Anti-B4-blocked ricin (anti-B4-bR) is an immunotoxin directed against CD19-positive cells that is currently being tested in several B-cell leukemia/lymphoma clinical trials. To explore the possibility of using anti-B4-bR in combination with chemotherapy protocols, we investigated the in vitro and in vivo cytotoxic effects of combining it with doxorubicin or etoposide using the lymphoma cell line Namalwa and a P-glycoprotein-expressing cell line, Namalwa/mdr-1, obtained by retroviral infection of Namalwa cells with the mdr-1 gene. Namalwa/mdr-1 cells were slightly more sensitive to anti-B4-bR t…

Dependence of ricin toxoid vaccine efficacy on the structure of poly(lactide-co-glycolide) microparticle carriers.

Biodegradable microparticles made of poly(lactide-co-glycolide) (PLG) were used for protracted and pulsed-release of the incorporated ricin toxoid (RT) vaccine to reduce the multiple immunization doses and the time required to induce complete protection against lethal aerosol-borne ricin challenge. The release rate of RT encapsulated in PLG microparticles was controlled by polymer selection and varying the preparation procedures, which allowed us to control microparticle size and the distribution of the vaccine in the polymeric matrix. PLG-microparticles in which RT vaccine was distributed het…

Monensin intercalation in liposomes: effect on cytotoxicities of ricin, Pseudomonas exotoxin A and diphtheria toxin in CHO cells.

Monensin, a carboxylic ionophore was intercalated in liposomes (liposomal monensin) and its effect on cytotoxicities of ricin, Pseudomonas exotoxin A and diphtheria toxin in CHO cells was studied. Intercalation of monensin in liposomal bilayer is found to have no effect on its stability and interaction with cells. Liposomal monensin (1 nM) substantially enhance the cytotoxicities of ricin (62-fold) and Pseudomonas exotoxin A (11.5-fold) while it has no effect on diphtheria toxin. This observed effect is highly dependent on the liposomal lipid composition. The potentiating ability of monensin (…

Investigating diversity and similarity between CBM13 modules and ricin-B lectin domains using sequence similarity networks.

BACKGROUND: The CBM13 family comprises carbohydrate-binding modules that occur mainly in enzymes and in several ricin-B lectins. The ricin-B lectin domain resembles the CBM13 module to a large extent. Historically, ricin-B lectins and CBM13 proteins were considered completely distinct, despite their structural and functional similarities. RESULTS: In this data mining study, we investigate structural and functional similarities of these intertwined protein groups. Because of the high structural and functional similarities, and differences in nomenclature usage in several databases, confusion c…

Stability and cytotoxicity of Fab-ricin A immunotoxins prepared with water soluble long chain heterobifunctional crosslinking agents.

The effects of the hindered and non-hindered water soluble long-chain disulfide bonds on the stability and cytotoxicity of the ricin A chain (RTA) immunotoxin were examined. The RTA immunotoxins were prepared with the Fab fragments of anti-common acute lymphoblastic leukemia antigen (CALLA) monoclonal antibody (Fab-RTA) using sulfosuccinimidyl-6-[(-methyl-(-(2-pyridyldithio)toluamido]hexanoate (S-LC-SMPT) and sulfosuccinimidyl-6-[3-(2-pyridyldithio)-propionamido]hexanoate (S-LC-SPDP). The prepared Fab-RTA immunotoxins were evaluated for their conjugation yield, immunoreactivity, thermal and di…

Ингибитор ретроградной торговли рицином и токсинами, подобными шиге, препятствует заражению клеток человеческими и обезьяньими полиомавирусами.

Полиомавирусы являются повсеместно распространенными патогенами, которые вызывают серьезные заболевания у иммунокомпромиссированных лиц. JC Poliomavirus (JCPyV) является источником причинно-следственной связи в связи со смертельным демиелинизирующим заболеванием прогрессивная многофукальная лейкоэнцефалопатия (PML), в то время как BK полиомавирус (BKPyV) вызывает полиомавирусную нефропатию и геморрагический цитит. Вакцины или антивирусная терапия, направленные на эти вирусы, отсутствуют, и лечение сосредоточено на устранении коренных причин иммунодепрессии. Мы демонстрируем, что ретро-2 (цикл)

Совпадение в аннотации оригинала
UNLABELLED: Polyomaviruses are ubiquitous pathogens that cause severe disease in immunocompromised individuals. JC polyomavirus (JCPyV) is t … cing the underlying causes of immunosuppression. We demonstrate that retro-2(cycl), an inhibitor of ricin and Shiga-like toxins (SLTs), inhibits infection by JCPyV, BKPyV, and simian virus 40. Retro-2(cycl) inhibits retrograde transport of polyomaviruses to the endoplasmic reticulum, a step necessary for productive infection. Retro-2(cycl) likely inhibi …

Efficacy of an anti-CD7-ricin A chain immunoconjugate in a novel murine model of human T-cell leukemia.

In vivo efficacy testing of monoclonal antibody-based drugs specific for human leukemias is hampered by the paucity of suitable animal model … ent of CEM-engrafted mice with 4A2-RTA30, an immunoconjugate of an anti-CD7 monoclonal antibody and ricin A chain (RTA30), resulted in a 100- to 200-fold overall depletion of CEM cells from the spleen and the bone marrow (P less than 0.02). This depletion was specific and toxin-dependent, as a control immunoconjugate had no demonstrable effect (P greate …

The binding of the B-chain of ricin to Burkitt lymphoma cells. A new approach to ligand-receptor interaction studies.

It is shown that conformational changes of receptor proteins brought about by binding of a ligand induce changes in the lipid environment of the receptor that can be monitored by fluorescent lipid probes. On this basis a new approach to studies of ligand-receptor binding is proposed. Using the interaction of the ricin B-chain with Burkitt lymphoma cells as an example and fluorescent labelled sphingomyelin as a probe, the ligand-induced changes of fluorescence anisotropy were shown to be concentration-dependent and to permit determination of the binding constant and the number of receptor-bindi…

Differential neutralizing activities of a single domain camelid antibody (VHH) specific for ricin toxin's binding subunit (RTB).

Ricin, a member of the A-B family of ribosome-inactivating proteins, is classified as a Select Toxin by the Centers for Disease Control and Prevention because of its potential use as a biothreat agent. In an effort to engineer therapeutics for ricin, we recently produced a collection of alpaca-derived, heavy-chain only antibody VH domains (VHH or "nanobody") specific for ricin's enzymatic (RTA) and binding (RTB) subunits. We reported that one particular RTB-specific VHH, RTB-B7, when covalently linked via a peptide spacer to different RTA-specific VHHs, resulted in heterodimers like VHH D10/B7…

Combination of two candidate subunit vaccine antigens elicits protective immunity to ricin and anthrax toxin in mice.

In an effort to develop combination vaccines for biodefense, we evaluated a ricin subunit antigen, RiVax, given in conjunction with an anthrax protective antigen, DNI. The combination led to high endpoint titer antibody response, neutralizing antibodies, and protective immunity against ricin and anthrax lethal toxin. This is a natural combination vaccine, since both antigens are recombinant subunit proteins that would be given to the same target population.

A new modular protein of Cryptosporidium parvum, with ricin B and LCCL domains, expressed in the sporozoite invasive stage.

The recombinant SA35 peptide has been described as an antigenic portion of a larger Cryptosporidium parvum protein. We identified and characterized the encoding Cpa135 gene and the entire protein, Cpa135. The Cpa135 gene was found to consist of a single exon of 4671 bp, and the mRNA transcribed in the sporozoites was identified. The predicted 1556 amino-acid protein showed the presence of domains which are widely conserved also in other unrelated phylogenetic groups (i.e. a ricin B and a LCCL motif). Comparison of Cpa135 sequence with genomic and protein databases revealed many related genes i…

Advancing subunit vaccine efficacy against ricin toxin with a novel DNA hydrogel adjuvant tandem assembly by CpG motifs.

The development of effective countermeasures against ricin toxin, a potent biological threat, remains a pressing public health challenge. Subunit vaccines based on the ricin toxin A subunit offer a favorable safety profile but often suffer from limited immunogenicity, necessitating advanced adjuvants to elicit protective immunity. Here, we report a novel injectable CpG-motif-based hydrogel that serves as both adjuvant and delivery vehicle for a mutated and truncated RTA antigen. This CpG-gel adjuvant, synthesized via rolling circle amplification, incorporated with guanine-rich sequences that c…

Discovery of RTA ricin subunit inhibitors: a computational study using PM7 quantum chemical method and steered molecular dynamics.

Ricin is a potent toxin derived from the castor bean plant and comprises two subunits, RTA and RTB. Because of its cytotoxicity, ricin has alarmed world authorities for its potential use as a chemical weapon. Ricin also affects castor bean agribusiness, given the risk of animal and human poisoning. Over the years, many groups attempted to propose small-molecules that bind to the RTA active site, the catalytic chain. Despite such efforts, there is still no effective countermeasure against ricin poisoning. The computational study carried out in the present work renews the discussion about small-…

Elimination of B-lineage leukemia and lymphoma cells from bone marrow grafts using anti-B4-blocked-ricin immunotoxin.

Bone marrow is the primary site of disease in patients with acute lymphoblastic leukemia (ALL) and is frequently involved in patients with non-Hodgkin's lymphoma (NHL). At the time of autologous bone marrow transplantation, marrow grafts from patients with leukemia and lymphoma are often still contaminated by malignant cells, even when such patients achieve complete clinical remission. In this study, we evaluated the potential of anti-B4-blocked-ricin (anti-B4-bR) immunotoxin to eliminate residual ALL and NHL cells from bone marrow. Anti-B4-bR binds to the CD19 antigen, which is B-lineage spec…