Special Issue "Toxins: Mr Hyde or Dr Jekyll?"

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

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 8423

Special Issue Editors

Dr. Daniel Ladant
E-Mail Website
Guest Editor
Institut Pasteur, Unité "Biochimie des Interactions Macromoléculaires", 25-28 Rue du Dr Roux, F-75015 Paris, France
Interests: Bordetella pertussis toxins; bacterial adenylate and nucleotidyl cyclases; RTX toxins; structure-function studies; toxin translocation
Special Issues, Collections and Topics in MDPI journals
Dr. Gilles Prévost
E-Mail Website
Guest Editor
Institut de Bactériologie, Unité UR-7290 "Virulence bactérienne précoce", ITI InnoVec, 3 rue Koeberlé, F-67000 Strasbourg, France
Interests: Staphylococcus aureus toxins; molecular action
Dr. Michel R. Popoff
E-Mail Website
Guest Editor
Institut Pasteur, Unité "Bactéries anaérobies et Toxines", 25-28 Rue du Dr Roux, F-75015 Paris, France
Interests: bacterial protein toxins; clostridial toxins; pore-forming toxins; cellular uptake of bacterial toxins; Rho-GTPases; interactions of clostridial toxins with the actin cytoskeleton; botulinum neurotoxins; passage of the neurotoxins through the epithelial barrier; regulation of clostridial toxin synthesis
Special Issues, Collections and Topics in MDPI journals
Dr. Evelyne Benoit
E-Mail Website
Guest Editor
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, ERL 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

Special Issue Information

Dear Colleagues, 

Toxins are biologically active substances produced by all kinds of living organisms such as bacteria, fungi, plants, and animals. They present a vast diversity of molecular structures and target a wide variety of receptors linked to physiological processes. Selected during evolution to give them a disabling/lethal effect, they display finely tuned functional properties in terms of affinity and selectivity.

Toxins are, therefore, very attractive compounds because they exhibit a Janus-like character, being both poisons and remedies, and, as a matter of fact, have been primarily investigated not only for the light they can throw on fundamental physiological processes, but also for their potential therapeutic applications. The Toxins Special Issue entitled “Toxins: Mr Hyde or Dr Jekyll?” will accept manuscripts describing recent advances concerning toxins of various origins (such as animal, bacterial, fungi, marine and plant toxins) and a variety of topics covering toxin structure and organization, toxin receptor/target, phylogeny, toxinogenesis regulation, medical application, toxin function/activity, and toxin delivery into cell. This Special Issue is open (but not limited) to oral communications and posters that will be presented during the virtual meeting of the French Society of Toxinology (SFET) that will be held on 9th and 10th December 2021 (e-RT27—27th SFET meeting).

Dr. Daniel Ladant
Dr. Gilles Prévost
Dr. Michel R. Popoff
Dr. Evelyne Benoit
Guest Editors

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 2400 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

  • animal toxins
  • bacterial toxins
  • marine toxins
  • plant toxins
  • toxin structure and organization
  • toxin receptor/target
  • phylogeny
  • toxinogenesis regulation
  • medical application
  • toxin function/activity
  • toxin delivery into cell

Published Papers (10 papers)

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Concept Paper
Effector-Triggered Trained Immunity: An Innate Immune Memory to Microbial Virulence Factors?
Toxins 2022, 14(11), 798; https://doi.org/10.3390/toxins14110798 - 17 Nov 2022
Viewed by 260
Abstract
In the last decade, a major dogma in the field of immunology has been called into question by the identification of a cell autonomous innate immune memory. This innate immune memory (also named trained immunity) was found to be mostly carried by innate [...] Read more.
In the last decade, a major dogma in the field of immunology has been called into question by the identification of a cell autonomous innate immune memory. This innate immune memory (also named trained immunity) was found to be mostly carried by innate immune cells and to be characterized by an exacerbated inflammatory response with a heightened expression of proinflammatory cytokines, including TNF-α, IL-6 and IL-1β. Unlike the vast majority of cytokines, IL-1β is produced as a proform (pro-IL-1β) and requires a proteolytic cleavage to exert its biological action. This cleavage takes place mainly within complex molecular platforms named inflammasomes. These platforms are assembled upon both the infectious or sterile activation of NOD-like receptors (NLRs), thereby allowing for the recruitment and activation of caspases and the subsequent maturation of pro-IL-1β into IL-1β. The NLRP3 inflammasome has recently been implicated both in western diet-induced trained immunity, and in the detection of microbial virulence factors (effector-triggered immunity (ETI)). Here, we will attempt to link these two immune processes and provide arguments to hypothesize the existence of trained immunity triggered by microbial virulence factors (effector-triggered trained immunity (ETTI)). Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
Article
A Robust and Sensitive Spectrophotometric Assay for the Enzymatic Activity of Bacterial Adenylate Cyclase Toxins
Toxins 2022, 14(10), 691; https://doi.org/10.3390/toxins14100691 - 08 Oct 2022
Viewed by 440
Abstract
Various bacterial pathogens are producing toxins that target the cyclic Nucleotide Monophosphate (cNMPs) signaling pathways in order to facilitate host colonization. Among them, several are exhibiting potent nucleotidyl cyclase activities that are activated by eukaryotic factors, such as the adenylate cyclase (AC) toxin, [...] Read more.
Various bacterial pathogens are producing toxins that target the cyclic Nucleotide Monophosphate (cNMPs) signaling pathways in order to facilitate host colonization. Among them, several are exhibiting potent nucleotidyl cyclase activities that are activated by eukaryotic factors, such as the adenylate cyclase (AC) toxin, CyaA, from Bordetella pertussis or the edema factor, EF, from Bacillus anthracis. The characterization of these toxins frequently requires accurate measurements of their enzymatic activity in vitro, in particular for deciphering their structure-to-function relationships by protein engineering and site-directed mutagenesis. Here we describe a simple and robust in vitro assay for AC activity based on the spectrophotometric detection of cyclic AMP (cAMP) after chromatographic separation on aluminum oxide. This assay can accurately detect down to fmol amounts of B. pertussis CyaA and can even be used in complex media, such as cell extracts. The relative advantages and disadvantages of this assay in comparison with other currently available methods are briefly discussed. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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Review
Regulatory Networks Controlling Neurotoxin Synthesis in Clostridium botulinum and Clostridium tetani
Toxins 2022, 14(6), 364; https://doi.org/10.3390/toxins14060364 - 24 May 2022
Cited by 1 | Viewed by 1205
Abstract
Clostridium botulinum and Clostridium tetani are Gram-positive, spore-forming, and anaerobic bacteria that produce the most potent neurotoxins, botulinum toxin (BoNT) and tetanus toxin (TeNT), responsible for flaccid and spastic paralysis, respectively. The main habitat of these toxigenic bacteria is the environment (soil, sediments, [...] Read more.
Clostridium botulinum and Clostridium tetani are Gram-positive, spore-forming, and anaerobic bacteria that produce the most potent neurotoxins, botulinum toxin (BoNT) and tetanus toxin (TeNT), responsible for flaccid and spastic paralysis, respectively. The main habitat of these toxigenic bacteria is the environment (soil, sediments, cadavers, decayed plants, intestinal content of healthy carrier animals). C. botulinum can grow and produce BoNT in food, leading to food-borne botulism, and in some circumstances, C. botulinum can colonize the intestinal tract and induce infant botulism or adult intestinal toxemia botulism. More rarely, C. botulinum colonizes wounds, whereas tetanus is always a result of wound contamination by C. tetani. The synthesis of neurotoxins is strictly regulated by complex regulatory networks. The highest levels of neurotoxins are produced at the end of the exponential growth and in the early stationary growth phase. Both microorganisms, except C. botulinum E, share an alternative sigma factor, BotR and TetR, respectively, the genes of which are located upstream of the neurotoxin genes. These factors are essential for neurotoxin gene expression. C. botulinum and C. tetani share also a two-component system (TCS) that negatively regulates neurotoxin synthesis, but each microorganism uses additional distinct sets of TCSs. Neurotoxin synthesis is interlocked with the general metabolism, and CodY, a master regulator of metabolism in Gram-positive bacteria, is involved in both clostridial species. The environmental and nutritional factors controlling neurotoxin synthesis are still poorly understood. The transition from amino acid to peptide metabolism seems to be an important factor. Moreover, a small non-coding RNA in C. tetani, and quorum-sensing systems in C. botulinum and possibly in C. tetani, also control toxin synthesis. However, both species use also distinct regulatory pathways; this reflects the adaptation of C. botulinum and C. tetani to different ecological niches. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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Article
Clostridium botulinum C3 Toxin for Selective Delivery of Cargo into Dendritic Cells and Macrophages
Toxins 2022, 14(10), 711; https://doi.org/10.3390/toxins14100711 - 18 Oct 2022
Viewed by 480
Abstract
The protein toxin C3bot from Clostridium botulinum is a mono-ADP-ribosyltransferase that selectively intoxicates monocyte-derived cells such as macrophages, osteoclasts, and dendritic cells (DCs) by cytosolic modification of Rho-A, -B, and -C. Here, we investigated the application of C3bot as well as its non-toxic [...] Read more.
The protein toxin C3bot from Clostridium botulinum is a mono-ADP-ribosyltransferase that selectively intoxicates monocyte-derived cells such as macrophages, osteoclasts, and dendritic cells (DCs) by cytosolic modification of Rho-A, -B, and -C. Here, we investigated the application of C3bot as well as its non-toxic variant C3botE174Q as transporters for selective delivery of cargo molecules into macrophages and DCs. C3bot and C3botE174Q facilitated the uptake of eGFP into early endosomes of human-monocyte-derived macrophages, as revealed by stimulated emission depletion (STED) super-resolution microscopy. The fusion of the cargo model peptide eGFP neither affected the cell-type selectivity (enhanced uptake into human macrophages ex vivo compared to lymphocytes) nor the cytosolic release of C3bot. Moreover, by cell fractionation, we demonstrated that C3bot and C3botE174Q strongly enhanced the cytosolic release of functional eGFP. Subsequently, a modular system was created on the basis of C3botE174Q for covalent linkage of cargos via thiol–maleimide click chemistry. The functionality of this system was proven by loading small molecule fluorophores or an established reporter enzyme and investigating the cellular uptake and cytosolic release of cargo. Taken together, non-toxic C3botE174Q is a promising candidate for the cell-type-selective delivery of small molecules, peptides, and proteins into the cytosol of macrophages and DCs. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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Review
Superantigens, a Paradox of the Immune Response
Toxins 2022, 14(11), 800; https://doi.org/10.3390/toxins14110800 - 18 Nov 2022
Viewed by 279
Abstract
Staphylococcal enterotoxins are a wide family of bacterial exotoxins with the capacity to activate as much as 20% of the host T cells, which is why they were called superantigens. Superantigens (SAgs) can cause multiple diseases in humans and cattle, ranging from mild [...] Read more.
Staphylococcal enterotoxins are a wide family of bacterial exotoxins with the capacity to activate as much as 20% of the host T cells, which is why they were called superantigens. Superantigens (SAgs) can cause multiple diseases in humans and cattle, ranging from mild to life-threatening infections. Almost all S. aureus isolates encode at least one of these toxins, though there is no complete knowledge about how their production is triggered. One of the main problems with the available evidence for these toxins is that most studies have been conducted with a few superantigens; however, the resulting characteristics are attributed to the whole group. Although these toxins share homology and a two-domain structure organization, the similarity ratio varies from 20 to 89% among different SAgs, implying wide heterogeneity. Furthermore, every attempt to structurally classify these proteins has failed to answer differential biological functionalities. Taking these concerns into account, it might not be appropriate to extrapolate all the information that is currently available to every staphylococcal SAg. Here, we aimed to gather the available information about all staphylococcal SAgs, considering their functions and pathogenicity, their ability to interact with the immune system as well as their capacity to be used as immunotherapeutic agents, resembling the two faces of Dr. Jekyll and Mr. Hyde. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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Article
Gambierol Blocks a K+ Current Fraction without Affecting Catecholamine Release in Rat Fetal Adrenomedullary Cultured Chromaffin Cells
Toxins 2022, 14(4), 254; https://doi.org/10.3390/toxins14040254 - 02 Apr 2022
Viewed by 831
Abstract
Gambierol inhibits voltage-gated K+ (KV) channels in various excitable and non-excitable cells. The purpose of this work was to study the effects of gambierol on single rat fetal (F19–F20) adrenomedullary cultured chromaffin cells. These excitable cells have different types of [...] Read more.
Gambierol inhibits voltage-gated K+ (KV) channels in various excitable and non-excitable cells. The purpose of this work was to study the effects of gambierol on single rat fetal (F19–F20) adrenomedullary cultured chromaffin cells. These excitable cells have different types of KV channels and release catecholamines. Perforated whole-cell voltage-clamp recordings revealed that gambierol (100 nM) blocked only a fraction of the total outward K+ current and slowed the kinetics of K+ current activation. The use of selective channel blockers disclosed that gambierol did not affect calcium-activated K+ (KCa) and ATP-sensitive K+ (KATP) channels. The gambierol concentration necessary to inhibit 50% of the K+ current-component sensitive to the polyether (IC50) was 5.8 nM. Simultaneous whole-cell current-clamp and single-cell amperometry recordings revealed that gambierol did not modify the membrane potential following 11s depolarizing current-steps, in both quiescent and active cells displaying repetitive firing of action potentials, and it did not increase the number of exocytotic catecholamine release events, with respect to controls. The subsequent addition of apamin and iberiotoxin, which selectively block the KCa channels, both depolarized the membrane and enhanced by 2.7 and 3.5-fold the exocytotic event frequency in quiescent and active cells, respectively. These results highlight the important modulatory role played by KCa channels in the control of exocytosis from fetal (F19–F20) adrenomedullary chromaffin cells. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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Article
The Role of Plasma Membrane Pleiotropic Drug Resistance Transporters in the Killer Activity of Debaryomyces hansenii and Wickerhamomyces anomalus Toxins
Toxins 2022, 14(3), 180; https://doi.org/10.3390/toxins14030180 - 28 Feb 2022
Viewed by 837
Abstract
The killer strains of Debaryomyces hansenii and Wickerhamomyces anomalus species secrete antimicrobial proteins called killer toxins which are active against selected fungal phytopathogens. In our research, we attempted to investigate the role of plasma membrane pleiotropic drug resistance (PDR) transporters (Pdr5p and Snq2p) [...] Read more.
The killer strains of Debaryomyces hansenii and Wickerhamomyces anomalus species secrete antimicrobial proteins called killer toxins which are active against selected fungal phytopathogens. In our research, we attempted to investigate the role of plasma membrane pleiotropic drug resistance (PDR) transporters (Pdr5p and Snq2p) in the mechanism of defense against killer toxins. Saccharomyces cerevisiae mutant strains with strengthened or weakened pleiotropic drug resistance due to increased or reduced number of mentioned PDR efflux pumps were tested for killer toxin susceptibility. The present study demonstrates the influence of the Snq2p efflux pump in immunity to W.anomalus BS91 killer toxin. It was also shown that the activity of killer toxins of D. hansenii AII4b, KI2a, MI1a and CBS767 strains is regulated by other transporters than those influencing W. anomalus killer toxin activity. In turn, this might be related to the functioning of the Pdr5p transporter and a complex cross-talk between several regulatory multidrug resistance networks. To the best of our knowledge, this is the first study that reports the involvement of PDR transporters in the cell membrane of susceptible microorganisms in resistance to killer yeasts’ toxins. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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Review
Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects
Toxins 2022, 14(10), 709; https://doi.org/10.3390/toxins14100709 - 17 Oct 2022
Viewed by 620
Abstract
Acid-sensing ion channels (ASICs) are voltage-independent H+-gated cation channels largely expressed in the nervous system of rodents and humans. At least six isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) associate into homotrimers or heterotrimers to form functional channels with highly [...] Read more.
Acid-sensing ion channels (ASICs) are voltage-independent H+-gated cation channels largely expressed in the nervous system of rodents and humans. At least six isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) associate into homotrimers or heterotrimers to form functional channels with highly pH-dependent gating properties. This review provides an update on the pharmacological profiles of animal peptide toxins targeting ASICs, including PcTx1 from tarantula and related spider toxins, APETx2 and APETx-like peptides from sea anemone, and mambalgin from snake, as well as the dimeric protein snake toxin MitTx that have all been instrumental to understanding the structure and the pH-dependent gating of rodent and human cloned ASICs and to study the physiological and pathological roles of native ASICs in vitro and in vivo. ASICs are expressed all along the pain pathways and the pharmacological data clearly support a role for these channels in pain. ASIC-targeting peptide toxins interfere with ASIC gating by complex and pH-dependent mechanisms sometimes leading to opposite effects. However, these dual pH-dependent effects of ASIC-inhibiting toxins (PcTx1, mambalgin and APETx2) are fully compatible with, and even support, their analgesic effects in vivo, both in the central and the peripheral nervous system, as well as potential effects in humans. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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Conference Report
Report from the 27th (Virtual) Meeting on Toxinology, “Toxins: Mr Hyde or Dr Jekyll?”, Organized by the French Society of Toxinology, 9–10 December 2021
Toxins 2022, 14(2), 110; https://doi.org/10.3390/toxins14020110 - 01 Feb 2022
Viewed by 998
Abstract
The French Society of Toxinology (SFET) organized its 27th annual meeting on 9–10 December 2021 as a virtual meeting (e-RT27). The central theme of this meeting was “Toxins: Mr Hyde or Dr Jekyll?”, emphasizing the latest findings on plant, fungal, algal, animal and [...] Read more.
The French Society of Toxinology (SFET) organized its 27th annual meeting on 9–10 December 2021 as a virtual meeting (e-RT27). The central theme of this meeting was “Toxins: Mr Hyde or Dr Jekyll?”, emphasizing the latest findings on plant, fungal, algal, animal and bacterial toxins during 10 lectures, 15 oral communications (shorter lectures) and 20 posters shared by ca. 80 participants. The abstracts of lectures and posters, as well as the winners of the best oral communication and poster awards, are presented in this report. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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Article
Chemical Synthesis of a Functional Fluorescent-Tagged α-Bungarotoxin
Toxins 2022, 14(2), 79; https://doi.org/10.3390/toxins14020079 - 21 Jan 2022
Viewed by 1176
Abstract
α-bungarotoxin is a large, 74 amino acid toxin containing five disulphide bridges, initially identified in the venom of Bungarus multicinctus snake. Like most large toxins, chemical synthesis of α-bungarotoxin is challenging, explaining why all previous reports use purified or recombinant α-bungarotoxin. However, only [...] Read more.
α-bungarotoxin is a large, 74 amino acid toxin containing five disulphide bridges, initially identified in the venom of Bungarus multicinctus snake. Like most large toxins, chemical synthesis of α-bungarotoxin is challenging, explaining why all previous reports use purified or recombinant α-bungarotoxin. However, only chemical synthesis allows easy insertion of non-natural amino acids or new chemical functionalities. Herein, we describe a procedure for the chemical synthesis of a fluorescent-tagged α-bungarotoxin. The full-length peptide was designed to include an alkyne function at the amino-terminus through the addition of a pentynoic acid linker. Chemical synthesis of α-bungarotoxin requires hydrazide-based coupling of three peptide fragments in successive steps. After completion of the oxidative folding, an azide-modified Cy5 fluorophore was coupled by click chemistry onto the toxin. Next, we determined the efficacy of the fluorescent-tagged α-bungarotoxin to block acetylcholine (ACh)-mediated currents in response to muscle nicotinic receptor activation in TE671 cells. Using automated patch-clamp recordings, we demonstrate that fluorescent synthetic α-bungarotoxin has the expected nanomolar affinity for the nicotinic receptor. The blocking effect of fluorescent α-bungarotoxin could be displaced by incubation with a 20-mer peptide mimicking the α-bungarotoxin binding site. In addition, TE671 cells could be labelled with fluorescent toxin, as witnessed by confocal microscopy, and this labelling was partially displaced by the 20-mer competitive peptide. We thus demonstrate that synthetic fluorescent-tagged α-bungarotoxin preserves excellent properties for binding onto muscle nicotinic receptors. Full article
(This article belongs to the Special Issue Toxins: Mr Hyde or Dr Jekyll?)
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