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Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins

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A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 48946

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Prof. Michel R. Popoff

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Bacterial Toxins, Institut Pasteur, 28 rue du Docteur Roux, Paris 75724, France
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Dr. Evelyne Benoit

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CEA, Institut des Sciences du Vivant Frédéric Joliot, Département Médicaments et Technologies pour la Santé (DMTS), Service d’Ingénierie Moléculaire pour la Santé (SIMoS), Université Paris-Saclay, EMR 9004 CNRS/CEA, F-91191 Gif-sur-Yvette, France
Interests: toxins; voltage-gated sodium channels; voltage-gated potassium channels; voltage-gated calcium channels; nicotinic acetylcholine receptors; venom toxins; marine toxins; bacterial toxins
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Toxins are very potent molecules responsible for moderate to highly severe diseases in man and animals. They are produced by a wide variety of organisms ranging from bacteria, to fungus, animals, and plants. However, toxins are also potent therapeutic drugs such as botulinum neurotoxins that have a large number of medical applications or peptide toxins, for example, conotoxins, used in the treatment of pain. In addition, toxins are very useful tools in cell biology that have revealed key physiological processes such as exocytosis, cytoskeleton organization, and the investigation of ionic channels. Modifications of toxins by bioengineering represent a current and important issue in the development of novel applications of toxins, including medical applications and tools for basic science, as well as the development of novel and efficient countermeasures (neutralizing antibodies and specific inhibitors). Recent progress shows that toxins can be modified for specific applications by increasing their activity or their cell specificity (for example, the development of toxins for the treatment of pain or the development of novel technological tools) or, in contrast, by decreasing their activity and use as vaccine or development of neutralizing antibodies and inhibitors.

Prof. Michel R. Popoff
Dr. Evelyne BENOIT
Guest Editors

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Keywords

bacterial toxins
animal toxins
plant toxins
venon peptides
neurotoxins
bioengineering
neutralizing antibodies
toxin inhibitors

Published Papers (12 papers)

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Research

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11 pages, 1345 KiB

Open AccessArticle

Effects of Modification of Light Parameters on the Production of Cryptophycin, Cyanotoxin with Potent Anticancer Activity, in Nostoc sp.

by Alexandros Polyzois, Diana Kirilovsky, Thi-hanh Dufat and Sylvie Michel

Toxins 2020, 12(12), 809; https://doi.org/10.3390/toxins12120809 - 21 Dec 2020

Cited by 8 | Viewed by 2483

Abstract

Cryptophycin-1 is a cyanotoxin produced by filamentous cyanobacteria. It has been evaluated as an anticancer agent with great potential. However, its synthesis provides insufficient yield for industrial use. An alternative solution for metabolite efficient production is to stress cyanobacteria by modifying the environmental conditions of the culture (Nostoc sp. ATCC 53789). Here, we examined the effects of light photoperiod, wavelength, and intensity. In light photoperiod, photoperiods 24:0 and 16:8 (light:dark) were tested while in wavelength, orange-red light was compared with blue. Medium, high, and very high light intensity experiments were performed to test the effect of light stress. For a 10-day period, growth was measured, metabolite concentration was calculated through HPLC, and the related curves were drawn. The differentiation of light wavelength had a major effect on the culture, as orange-red filter contributed to noticeable increase in both growth and doubled the cyanotoxin concentration in comparison to blue light. Remarkably, constant light provides higher cryptophycin yield, but slightly lower growth rate. Lastly, the microorganism prefers medium light intensities for both growth and metabolite expression. The combination of these optimal conditions would contribute to the further exploitation of cryptophycin. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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22 pages, 5295 KiB

Open AccessArticle

The 25 kDa H_CN Domain of Clostridial Neurotoxins Is Indispensable for Their Neurotoxicity

by Julian Deppe, Jasmin Weisemann, Stefan Mahrhold and Andreas Rummel

Toxins 2020, 12(12), 743; https://doi.org/10.3390/toxins12120743 - 26 Nov 2020

Cited by 4 | Viewed by 2335

Abstract

The extraordinarily potent clostridial neurotoxins (CNTs) comprise tetanus neurotoxin (TeNT) and the seven established botulinum neurotoxin serotypes (BoNT/A-G). They are composed of four structurally independent domains: the roles of the catalytically active light chain, the translocation domain H_N, and the C-terminal receptor binding domain H_CC are largely resolved, but that of the H_CN domain sandwiched between H_N and H_CC has remained unclear. Here, mutants of BoNT/A, BoNT/B, and TeNT were generated by deleting their H_CN domains or swapping H_CN domains between each other. Both deletion and replacement of TeNT H_CN domain by H_CNA and H_CNB reduced the biological activity similarly, by ~95%, whereas BoNT/A and B deletion mutants displayed >500-fold reduced activity in the mouse phrenic nerve hemidiaphragm assay. Swapping H_CN domains between BoNT/A and B hardly impaired their biological activity, but substitution with H_CNT did. Binding assays revealed that in the absence of H_CN, not all receptor binding sites are equally well accessible. In conclusion, the presence of H_CN is vital for CNTs to exert their neurotoxicity. Although structurally similar, the H_CN domain of TeNT cannot equally substitute those of BoNT and vice versa, leaving the possibility that H_CNT plays a different role in the intoxication mechanism of TeNT. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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13 pages, 2205 KiB

Open AccessArticle

Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors

by Jonathan R. Davies, Geoffrey Masuyer and Pål Stenmark

Toxins 2020, 12(9), 603; https://doi.org/10.3390/toxins12090603 - 17 Sep 2020

Cited by 5 | Viewed by 3224

Abstract

Botulinum neurotoxins (BoNTs) can be used therapeutically to treat a wide range of neuromuscular and neurological conditions. A collection of natural BoNT variants exists which can be classified into serologically distinct serotypes (BoNT/B), and further divided into subtypes (BoNT/B1, B2, …). BoNT subtypes share a high degree of sequence identity within the same serotype yet can display large variation in toxicity. One such example is BoNT/B2, which was isolated from Clostridium botulinum strain 111 in a clinical case of botulism, and presents a 10-fold lower toxicity than BoNT/B1. In an effort to understand the molecular mechanisms behind this difference in potency, we here present the crystal structures of BoNT/B2 in complex with the ganglioside receptor GD1a, and with the human synaptotagmin I protein receptor. We show, using receptor-binding assays, that BoNT/B2 has a slightly higher affinity for GD1a than BoNT/B1, and confirm its considerably weaker affinity for its protein receptors. Although the overall receptor-binding mechanism is conserved for both receptors, structural analysis suggests the lower affinity of BoNT/B2 is the result of key substitutions, where hydrophobic interactions important for synaptotagmin-binding are replaced by polar residues. This study provides a template to drive the development of future BoNT therapeutic molecules centered on assessing the natural subtype variations in receptor-binding that appears to be one of the principal stages driving toxicity. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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17 pages, 3733 KiB

Open AccessArticle

Clostridial C3 Toxins Enter and Intoxicate Human Dendritic Cells

by Maximilian Fellermann, Christina Huchler, Lea Fechter, Tobias Kolb, Fanny Wondany, Daniel Mayer, Jens Michaelis, Steffen Stenger, Kevin Mellert, Peter Möller, Thomas F. E. Barth, Stephan Fischer and Holger Barth

Toxins 2020, 12(9), 563; https://doi.org/10.3390/toxins12090563 - 01 Sep 2020

Cited by 7 | Viewed by 3636

Abstract

C3 protein toxins produced by Clostridium (C.) botulinum and C. limosum are mono-ADP-ribosyltransferases, which specifically modify the GTPases Rho A/B/C in the cytosol of monocytic cells, thereby inhibiting Rho-mediated signal transduction in monocytes, macrophages, and osteoclasts. C3 toxins are selectively taken up into the cytosol of monocytic cells by endocytosis and translocate from acidic endosomes into the cytosol. The C3-catalyzed ADP-ribosylation of Rho proteins inhibits essential functions of these immune cells, such as migration and phagocytosis. Here, we demonstrate that C3 toxins enter and intoxicate dendritic cells in a time- and concentration-dependent manner. Both immature and mature human dendritic cells efficiently internalize C3 exoenzymes. These findings could also be extended to the chimeric fusion toxin C2IN-C3lim. Moreover, stimulated emission depletion (STED) microscopy revealed the localization of the internalized C3 protein in endosomes and emphasized its potential use as a carrier to deliver foreign proteins into dendritic cells. In contrast, the enzyme C2I from the binary C. botulinum C2 toxin was not taken up into dendritic cells, indicating the specific uptake of C3 toxins. Taken together, we identified human dendritic cells as novel target cells for clostridial C3 toxins and demonstrated the specific uptake of these toxins via endosomal vesicles. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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14 pages, 2601 KiB

Open AccessArticle

Purification, Toxicity and Functional Characterization of a New Proteinaceous Mussel Biotoxin from Bizerte Lagoon

by Riadh Marrouchi, Evelyne Benoit, Sébastien Schlumberger, Zeineb Marzougui, Jean-Pierre Le Caer, Jordi Molgó and Riadh Kharrat

Toxins 2020, 12(8), 487; https://doi.org/10.3390/toxins12080487 - 30 Jul 2020

Viewed by 2974

Abstract

The marine environment is known to be occupied by microorganisms. The potential toxicity of some of these marine microorganisms, that are capable of producing unknown biotoxins, has always been underestimated. Indeed, these biotoxins may be a threat to human health through the consumption of contaminated seafood and fish. For more than ten years, recurrent but atypical toxicity has been detected in mussels from Bizerte lagoon (North of Tunisia) during routine tests. In this study, we have isolated and characterized a new proteinaceous marine biotoxin, named Mussel Toxic Peptide (MTP). Using HPLC, electrophoresis and LC/MS studies, we showed that MTP has a protein characteristic UV-spectrum, can be visualized by protein specific reagents such as Coomassie, and has a molecular mass of 6.4 kDa. Patch-clamp experiments performed on cultured N18 neuroblastoma cells revealed that MTP (0.9–18 µM) markedly inhibited voltage-gated Na current, but was about 23 times less active in blocking voltage-gated K current at equimolar concentrations. To the best of our knowledge, this is the first time that a proteinaceous marine biotoxin with relatively high molecular mass is isolated and involved in the contamination of mussels harvested from shellfish farming areas. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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14 pages, 3075 KiB

Open AccessArticle

Crystal Structure of Exotoxin A from Aeromonas Pathogenic Species

by Geoffrey Masuyer

Toxins 2020, 12(6), 397; https://doi.org/10.3390/toxins12060397 - 15 Jun 2020

Cited by 7 | Viewed by 4355

Abstract

Aeromonas exotoxin A (AE) is a bacterial virulence factor recently discovered in a clinical case of necrotising fasciitis caused by the flesh-eating Aeromonas hydrophila. Here, database mining shows that AE is present in the genome of several emerging Aeromonas pathogenic species. The X-ray crystal structure of AE was solved at 2.3 Å and presents all the hallmarks common to diphthamide-specific mono-ADP-ribosylating toxins, suggesting AE is a fourth member of this family alongside the diphtheria toxin, Pseudomonas exotoxin A and cholix. Structural homology indicates AE may use a similar mechanism of cytotoxicity that targets eukaryotic elongation factor 2 and thus inhibition of protein synthesis. The structure of AE also highlights unique features including a metal binding site, and a negatively charged cleft that could play a role in interdomain interactions and may affect toxicity. This study raises new opportunities to engineer alternative toxin-based molecules with pharmaceutical potential. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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14 pages, 2566 KiB

Open AccessArticle

Involvement of the Endothelin Receptor Type A in the Cardiovascular Inflammatory Response Following Scorpion Envenomation

by Amina Sifi, Sonia Adi-Bessalem and Fatima Laraba-Djebari

Toxins 2020, 12(6), 389; https://doi.org/10.3390/toxins12060389 - 12 Jun 2020

Cited by 4 | Viewed by 2358

Abstract

Elevated levels of endothelin-1 (ET-1) were recorded in sera of scorpion sting patients. However, no studies focused on the mechanism of ET-1 involvement in the pathogenesis of scorpion envenomation, particularly in the cardiovascular system which is seriously affected in severe cases of scorpion stings. Inflammation induced by Androctonus australis hector (Aah) scorpion venom in the heart together with the aorta was studied in mice pretreated with a specific endothelin A receptor (ETA-R) inhibitor. ETA-R inhibition resulted in the attenuation of the high amounts of cytokine (tumor necrosis factor alpha (TNF-α) and interleukin-17 (IL-17)) recorded in the sera of envenomed mice. The recovery of the oxidative stress marker balance and matrix metalloproteinase (MMP) expression were also observed, concomitantly with the reduction of tissular neutrophil infiltration. Additionally, the cardiac and the aortic tissue alterations, and the metabolic enzymes (creatine kinase (CK) and muscle–brain isoform creatine kinase (CK-MB)) overspread into sera were significantly attenuated. Obtained results suggest the implication of endothelin throughout its ETA receptors in the inflammatory response observed in the cardiovascular components during scorpion envenomation. Further knowledge is needed to better understand the implication of the endothelin axis and to improve the therapeutic management of severe scorpion sting cases. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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26 pages, 6700 KiB

Open AccessArticle

Tetanus Toxin Synthesis is Under the Control of A Complex Network of Regulatory Genes in Clostridium tetani

by Diana Chapeton-Montes, Lucile Plourde, Cecile Deneve, Dominique Garnier, Fabien Barbirato, Vincent Colombié, Sandy Demay, Georges Haustant, Olivier Gorgette, Christine Schmitt, Catherine Thouvenot, Holger Brüggemann and Michel R. Popoff

Toxins 2020, 12(5), 328; https://doi.org/10.3390/toxins12050328 - 15 May 2020

Cited by 8 | Viewed by 8796

Abstract

Clostridium tetani produces a potent neurotoxin, the tetanus toxin (TeNT), which is responsible for an often-fatal neurological disease (tetanus) characterized by spastic paralysis. Prevention is efficiently acquired by vaccination with the TeNT toxoid, which is obtained by C. tetani fermentation and subsequent purification and chemical inactivation. C. tetani synthesizes TeNT in a regulated manner. Indeed, the TeNT gene (tent) is mainly expressed in the late exponential and early stationary growth phases. The gene tetR (tetanus regulatory gene), located immediately upstream of tent, encodes an alternative sigma factor which was previously identified as a positive regulator of tent. In addition, the genome of C. tetani encodes more than 127 putative regulators, including 30 two-component systems (TCSs). Here, we investigated the impact of 12 regulators on TeNT synthesis which were selected based on their homology with related regulatory elements involved in toxin production in other clostridial species. Among nine TCSs tested, three of them impact TeNT production, including two positive regulators that indirectly stimulate tent and tetR transcription. One negative regulator was identified that interacts with both tent and tetR promoters. Two other TCSs showed a moderate effect: one binds to the tent promoter and weakly increases the extracellular TeNT level, and another one has a weak inverse effect. In addition, CodY (control of dciA (decoyinine induced operon) Y) but not Spo0A (sporulation stage 0) or the DNA repair protein Mfd (mutation frequency decline) positively controls TeNT synthesis by interacting with the tent promoter. Moreover, we found that inorganic phosphate and carbonate are among the environmental factors that control TeNT production. Our data show that TeNT synthesis is under the control of a complex network of regulators that are largely distinct from those involved in the control of toxin production in Clostridium botulinum or Clostridium difficile. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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Review

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19 pages, 16481 KiB

Open AccessReview

Shiga Toxins: An Update on Host Factors and Biomedical Applications

by Yang Liu, Songhai Tian, Hatim Thaker and Min Dong

Toxins 2021, 13(3), 222; https://doi.org/10.3390/toxins13030222 - 18 Mar 2021

Cited by 19 | Viewed by 5386

Abstract

Shiga toxins (Stxs) are classic bacterial toxins and major virulence factors of toxigenic Shigella dysenteriae and enterohemorrhagic Escherichia coli (EHEC). These toxins recognize a glycosphingolipid globotriaosylceramide (Gb3/CD77) as their receptor and inhibit protein synthesis in cells by cleaving 28S ribosomal RNA. They are the major cause of life-threatening complications such as hemolytic uremic syndrome (HUS), associated with severe cases of EHEC infection, which is the leading cause of acute kidney injury in children. The threat of Stxs is exacerbated by the lack of toxin inhibitors and effective treatment for HUS. Here, we briefly summarize the Stx structure, subtypes, in vitro and in vivo models, Gb3 expression and HUS, and then introduce recent studies using CRISPR-Cas9-mediated genome-wide screens to identify the host cell factors required for Stx action. We also summarize the latest progress in utilizing and engineering Stx components for biomedical applications. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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12 pages, 1783 KiB

Open AccessReview

Bioengineering of Bordetella pertussis Adenylate Cyclase Toxin for Vaccine Development and Other Biotechnological Purposes

by Daniel Ladant

Toxins 2021, 13(2), 83; https://doi.org/10.3390/toxins13020083 - 22 Jan 2021

Cited by 6 | Viewed by 3184

Abstract

The adenylate cyclase toxin, CyaA, is one of the key virulent factors produced by Bordetella pertussis, the causative agent of whooping cough. This toxin primarily targets innate immunity to facilitate bacterial colonization of the respiratory tract. CyaA exhibits several remarkable characteristics that have been exploited for various applications in vaccinology and other biotechnological purposes. CyaA has been engineered as a potent vaccine vehicle to deliver antigens into antigen-presenting cells, while the adenylate cyclase catalytic domain has been used to design a robust genetic assay for monitoring protein–protein interactions in bacteria. These two biotechnological applications are briefly summarized in this chapter. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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19 pages, 9502 KiB

Open AccessReview

Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development

by Christine Rasetti-Escargueil and Michel R. Popoff

Toxins 2021, 13(1), 1; https://doi.org/10.3390/toxins13010001 - 22 Dec 2020

Cited by 12 | Viewed by 4106

Abstract

Botulinum neurotoxins (BoNTs) show increasing therapeutic applications ranging from treatment of locally paralyzed muscles to cosmetic benefits. At first, in the 1970s, BoNT was used for the treatment of strabismus, however, nowadays, BoNT has multiple medical applications including the treatment of muscle hyperactivity such as strabismus, dystonia, movement disorders, hemifacial spasm, essential tremor, tics, cervical dystonia, cerebral palsy, as well as secretory disorders (hyperhidrosis, sialorrhea) and pain syndromes such as chronic migraine. This review summarizes current knowledge related to engineering of botulinum toxins, with particular emphasis on their potential therapeutic applications for pain management and for retargeting to non-neuronal tissues. Advances in molecular biology have resulted in generating modified BoNTs with the potential to act in a variety of disorders, however, in addition to the modifications of well characterized toxinotypes, the diversity of the wild type BoNT toxinotypes or subtypes, provides the basis for innovative BoNT-based therapeutics and research tools. This expanding BoNT superfamily forms the foundation for new toxins candidates in a wider range of therapeutic options. Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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30 pages, 2465 KiB

Open AccessMeeting Report

Report from the 26th Meeting on Toxinology, “Bioengineering of Toxins”, Organized by the French Society of Toxinology (SFET) and Held in Paris, France, 4–5 December 2019

by Pascale Marchot, Sylvie Diochot, Michel R. Popoff and Evelyne Benoit

Toxins 2020, 12(1), 31; https://doi.org/10.3390/toxins12010031 - 03 Jan 2020

Viewed by 4893

Abstract

This 26th edition of the annual Meeting on Toxinology (RT26) of the SFET (http://sfet.asso.fr/international) was held at the Institut Pasteur of Paris on 4–5 December 2019 [...] Full article

(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)

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