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Human monoclonal antibodies were used here to study the mechanism of neuron intoxication by tetanus neurotoxin protein toxins and as a safe preventive and therapeutic substitute of hyperimmune sera. By screening memory B cells of immune donors, we selected two monoclonal antibodies specific for tetanus neurotoxin with exceptionally high neutralizing activities, which have been extensively characterized both structurally and functionally. We found that these antibodies interfere with the binding and translocation of the neurotoxin into neurons by interacting with two epitopes, whose definition pinpoints crucial events in the cellular pathogenesis of tetanus. Some mechanistic aspects of tetanus neurotoxin intoxication were revealed, explaining at the same time, the unprecedented neutralization ability of these antibodies. Importantly, these antibodies are exceptionally efficient in preventing experimental tetanus when injected in mice long before the neurotoxin. Moreover, their Fab derivatives neutralize tetanus neurotoxin in post-exposure experiments, suggesting their potential therapeutic use upon intrathecal injection. As such, these human monoclonal antibodies, as well as their Fab derivatives, meet all requirements for being considered for prophylaxis and therapy of human tetanus and are ready for clinical trials.
Marco Pirazzini; Alessandro Grinzato; Davide Corti; Sonia Barbieri; Oneda Leka; Francesca Vallese; Marika Tonellato; Chiara Silacci-Fregni; Luca Piccoli; Eaazhisai Kandiah; Giampietro Schiavo; Giuseppe Zanotti; Antonio Lanzavecchia; Cesare Montecucco. Extremely potent Human Monoclonal Antibodies for the Prophylaxis and Therapy of Tetanus. 2021, 1 .
AMA StyleMarco Pirazzini, Alessandro Grinzato, Davide Corti, Sonia Barbieri, Oneda Leka, Francesca Vallese, Marika Tonellato, Chiara Silacci-Fregni, Luca Piccoli, Eaazhisai Kandiah, Giampietro Schiavo, Giuseppe Zanotti, Antonio Lanzavecchia, Cesare Montecucco. Extremely potent Human Monoclonal Antibodies for the Prophylaxis and Therapy of Tetanus. . 2021; ():1.
Chicago/Turabian StyleMarco Pirazzini; Alessandro Grinzato; Davide Corti; Sonia Barbieri; Oneda Leka; Francesca Vallese; Marika Tonellato; Chiara Silacci-Fregni; Luca Piccoli; Eaazhisai Kandiah; Giampietro Schiavo; Giuseppe Zanotti; Antonio Lanzavecchia; Cesare Montecucco. 2021. "Extremely potent Human Monoclonal Antibodies for the Prophylaxis and Therapy of Tetanus." , no. : 1.
Tetanus is a deadly but preventable disease caused by a protein neurotoxin produced by Clostridium tetani. Spores of C. tetani may contaminate a necrotic wound and germinate into a vegetative bacterium that releases a toxin, termed tetanus neurotoxin (TeNT). TeNT enters the general circulation, binds to peripheral motor neurons and sensory neurons, and is transported retroaxonally to the spinal cord. It then enters inhibitory interneurons and blocks the release of glycine or GABA causing a spastic paralysis. This review attempts to correlate the metalloprotease activity of TeNT and its trafficking and localization into the vertebrate body to the nature and sequence of appearance of the symptoms of tetanus.
Aram Megighian; Marco Pirazzini; Federico Fabris; Ornella Rossetto; Cesare Montecucco. Tetanus and tetanus neurotoxin: From peripheral uptake to central nervous tissue targets. Journal of Neurochemistry 2021, 1 .
AMA StyleAram Megighian, Marco Pirazzini, Federico Fabris, Ornella Rossetto, Cesare Montecucco. Tetanus and tetanus neurotoxin: From peripheral uptake to central nervous tissue targets. Journal of Neurochemistry. 2021; ():1.
Chicago/Turabian StyleAram Megighian; Marco Pirazzini; Federico Fabris; Ornella Rossetto; Cesare Montecucco. 2021. "Tetanus and tetanus neurotoxin: From peripheral uptake to central nervous tissue targets." Journal of Neurochemistry , no. : 1.
Melatonin is an ancient multi‐tasking molecule produced by the pineal gland and by several extrapineal tissues. A variety of activities has been ascribed to this hormone in different physiological and pathological contexts, but little is know about its role in peripheral neuroregeneration. Here we have exploited two different types of injury to test the capability of melatonin to stimulate regeneration of motor axons: i) the acute and reversible presynaptic degeneration induced by the spider neurotoxin α‐Latrotoxin, and ii) the compression/transection of the sciatic nerve. We found that in both cases melatonin administration accelerates the process of nerve repair. This pro‐regenerative action is MT1‐mediated, and at least in part due to a sustained activation of the ERK1/2 pathway. These findings reveal a receptor‐mediated, pro‐regenerative action of melatonin in vivo that holds important clinical implications, as it posits melatonin as a safe candidate molecule for the treatment of a number of peripheral neurodegenerative conditions.
Marco Stazi; Samuele Negro; Aram Megighian; Giorgia D'este; Michele Solimena; Ralf Jockers; Florigio Lista; Cesare Montecucco; Michela Rigoni. Melatonin promotes regeneration of injured motor axons via MT 1 receptors. Journal of Pineal Research 2020, 70, 1 .
AMA StyleMarco Stazi, Samuele Negro, Aram Megighian, Giorgia D'este, Michele Solimena, Ralf Jockers, Florigio Lista, Cesare Montecucco, Michela Rigoni. Melatonin promotes regeneration of injured motor axons via MT 1 receptors. Journal of Pineal Research. 2020; 70 (1):1.
Chicago/Turabian StyleMarco Stazi; Samuele Negro; Aram Megighian; Giorgia D'este; Michele Solimena; Ralf Jockers; Florigio Lista; Cesare Montecucco; Michela Rigoni. 2020. "Melatonin promotes regeneration of injured motor axons via MT 1 receptors." Journal of Pineal Research 70, no. 1: 1.
Envenomation by snakes is a major neglected human disease. Hospitalization and use of animal-derived antivenom are the primary therapeutic supports currently available. There is consensus that additional, not expensive, treatments that can be delivered even long after the snake bite are needed. We recently showed that the drug dubbed NUCC-390 shortens the time of recovery from the neuroparalysis caused by traumatic or toxic degeneration of peripheral motor neurons. These syndromes are characterized by the activation of a pro-regenerative molecular axis, consisting of the CXCR4 receptor expressed at the damaged site in neuronal axons and by the release of its ligand CXCL12α, produced by surrounding Schwann cells. This intercellular signaling axis promotes axonal growth and functional recovery from paralysis. NUCC-390 is an agonist of CXCR4 acting similarly to CXCL12α. Here, we have tested its efficacy in a murine model of neuroparalytic envenoming by a Papuan Taipan (Oxyuranus scutellatus) where a degeneration of the motor axon terminals caused by the presynaptic PLA2 toxin Taipoxin, contained in the venom, occurs. Using imaging of the neuromuscular junction and electrophysiological analysis, we found that NUCC-390 administration after injection of either the purified neuroparalytic Taipoxin or the whole Taipan venom, significantly accelerates the recovery from paralysis. These results indicate that NUCC-390, which is non-toxic in mice, should be considered for trials in humans to test its efficacy in accelerating the recovery from the peripheral neuroparalysis induced by Taipans. NUCC-390 should be tested as well in the envenomation by other snakes that cause neuroparalytic syndromes in humans. NUCC-390 could become an additional treatment, common to many snake envenomings, that can be delivered after the bite to reduce death by respiratory deficits and to shorten and improve functional recovery. We have taken here a different angle in the search for novel treatments of snake envenomings by focusing of the phase of recovery from the peripheral neuroparalysis caused by neurotoxic snakes. This is a critical period that may require mechanical ventilation and prolonged hospitalization. We have found a drug, dubbed NUCC-390, which accelerates the functional recovery from peripheral neuroparalysis caused by the Taipan venom in mice, by acting on the CXCR4 receptor. In fact, we found here that this receptor is expressed by the motor neuron at the site of damage that, in the case of many snake venoms containing presynaptic PLA2 neurotoxins, consists in the degeneration of the axon terminal. NUCC-390 binds to CXCR4 and acts similarly to its natural agonist the chemokine CXCL12α. The compound is not toxic and can be administered after the snakebite and therefore it has the potential of becoming a non-expensive addition to the currently available antisera treatment whose efficacy is limited by the need of delivery shortly after snakebite.
Marco Stazi; Giorgia D’Este; Andrea Mattarei; Samuele Negro; Florigio Lista; Michela Rigoni; Aram Megighian; Cesare Montecucco. An agonist of the CXCR4 receptor accelerates the recovery from the peripheral neuroparalysis induced by Taipan snake envenomation. PLOS Neglected Tropical Diseases 2020, 14, e0008547 .
AMA StyleMarco Stazi, Giorgia D’Este, Andrea Mattarei, Samuele Negro, Florigio Lista, Michela Rigoni, Aram Megighian, Cesare Montecucco. An agonist of the CXCR4 receptor accelerates the recovery from the peripheral neuroparalysis induced by Taipan snake envenomation. PLOS Neglected Tropical Diseases. 2020; 14 (9):e0008547.
Chicago/Turabian StyleMarco Stazi; Giorgia D’Este; Andrea Mattarei; Samuele Negro; Florigio Lista; Michela Rigoni; Aram Megighian; Cesare Montecucco. 2020. "An agonist of the CXCR4 receptor accelerates the recovery from the peripheral neuroparalysis induced by Taipan snake envenomation." PLOS Neglected Tropical Diseases 14, no. 9: e0008547.
Eubacterium tarantellae was originally cultivated from the brain of fish affected by twirling movements. Here, we present the draft genome sequence of E. tarantellae DSM 3997, which consists of 3,982,316 bp. Most protein-coding genes in this strain are similar to genes of Clostridium bacteria, supporting the renaming of E. tarantellae as Clostridium tarantellae .
Luca Bano; Matthias Kiel; Gabriele Sales; Andrew C. Doxey; Michael Mansfield; Haleluya T. Wami; Marco Schiavone; Ornella Rossetto; Marco Pirazzini; Ulrich Dobrindt; Cesare Montecucco. Genome Sequence of the Fish Brain Bacterium Clostridium tarantellae. Microbiology Resource Announcements 2020, 9, 1 .
AMA StyleLuca Bano, Matthias Kiel, Gabriele Sales, Andrew C. Doxey, Michael Mansfield, Haleluya T. Wami, Marco Schiavone, Ornella Rossetto, Marco Pirazzini, Ulrich Dobrindt, Cesare Montecucco. Genome Sequence of the Fish Brain Bacterium Clostridium tarantellae. Microbiology Resource Announcements. 2020; 9 (16):1.
Chicago/Turabian StyleLuca Bano; Matthias Kiel; Gabriele Sales; Andrew C. Doxey; Michael Mansfield; Haleluya T. Wami; Marco Schiavone; Ornella Rossetto; Marco Pirazzini; Ulrich Dobrindt; Cesare Montecucco. 2020. "Genome Sequence of the Fish Brain Bacterium Clostridium tarantellae." Microbiology Resource Announcements 9, no. 16: 1.
Botulinum neurotoxins (BoNTs) are a growing family of bacterial protein toxins that cause botulism, a rare but often fatal animal and human disease. They are the most potent toxins known owing to their molecular architecture, which underlies their mechanism of action. BoNTs target peripheral nerve terminals by a unique mode of binding and enter into their cytosol where they cleave SNARE proteins, thus inhibiting the neurotransmitter release. The specificity and rapidity of binding, which limits the anatomical area of its neuroparalytic action, and its reversible action make BoNT a valuable pharmaceutical to treat neurological and non-neurological diseases determined by hyperactivity of cholinergic nerve terminals. This review reports the progress on our understanding of how BoNTs cause nerve paralysis highlighting the different steps of their molecular mechanism of action as key aspects to explain their extreme toxicity but also their unique pharmacological properties.
O. Rossetto; M. Pirazzini; F. Fabris; C. Montecucco. Botulinum Neurotoxins: Mechanism of Action. Botulinum Toxin Therapy 2020, 35 -47.
AMA StyleO. Rossetto, M. Pirazzini, F. Fabris, C. Montecucco. Botulinum Neurotoxins: Mechanism of Action. Botulinum Toxin Therapy. 2020; ():35-47.
Chicago/Turabian StyleO. Rossetto; M. Pirazzini; F. Fabris; C. Montecucco. 2020. "Botulinum Neurotoxins: Mechanism of Action." Botulinum Toxin Therapy , no. : 35-47.
The Botulinum NeuroToxin (BoNT) comprises several serotypes with distinct properties, mechanisms of action, sensitivity and duration of effect in different species. The serotype A (BoNT/A) is the prevalent neurotoxin applied in human's disease. In this paper we present an overview of the current knowledge regarding the duration of effect and the neuromuscular sprouting of different BoNT serotypes in humans. Then, we report the original results of a study in healthy subjects treated with BoNT/A, B, C and F using different neurophysiological techniques. Twelve healthy volunteers (7 men, 5 women) are treated with BoNT/A, B, C and F or placebo in Abductor digiti minimi (ADM) muscle of the hand. Before and after injections, an extensive neurophysiological study is performed with the CMAP amplitude variation, Multi-Motor Unit Action Potentials (MUAPs) analysis, the Turns/Amplitude ratio of interference pattern (IP) and determination of jitter and Fiber Density (FD) at single-fiber electromyography (SFEMG), at week 2 (w2), 4 (w4), 6 (w6) and 8 (w8). A maximal neuromuscular block is obtained at w2 for all the serotypes. Afterwards, the CMAP trend appear similar for BoNT/A, B, and C while, BoNT/F shows a faster recover. Multi-MUAPs analysis and IP detect mild changes at w2 for all serotypes, except for BoNT/F that shows a greater change since w4. SFEMG have minimal changes in FD while, Jitter increase at w2 with a slower decrease over the time for all BoNTs. In conclusion, BoNT/F has earlier sprouting and complete recovery at w8. Other serotypes present a slower and similar profile. The EMG appear useful to study the functional recovery in humans, and these results should provide new evidence for assessing different serotypes. These findings improve our knowledge regarding the methods to evaluate duration of effects and dose equivalents in different serotypes, that in the future could change the clinicians strategy for disease-tailored BoNT therapies.
Roberto Eleopra; Sara Rinaldo; Cesare Montecucco; Ornella Rossetto; Grazia Devigili. Clinical duration of action of different botulinum toxin types in humans. Toxicon 2020, 179, 84 -91.
AMA StyleRoberto Eleopra, Sara Rinaldo, Cesare Montecucco, Ornella Rossetto, Grazia Devigili. Clinical duration of action of different botulinum toxin types in humans. Toxicon. 2020; 179 ():84-91.
Chicago/Turabian StyleRoberto Eleopra; Sara Rinaldo; Cesare Montecucco; Ornella Rossetto; Grazia Devigili. 2020. "Clinical duration of action of different botulinum toxin types in humans." Toxicon 179, no. : 84-91.
Ornella Rossetto; Cesare Montecucco. Botulinum Neurotoxins. Encyclopedia of Molecular Pharmacology 2020, 1 -9.
AMA StyleOrnella Rossetto, Cesare Montecucco. Botulinum Neurotoxins. Encyclopedia of Molecular Pharmacology. 2020; ():1-9.
Chicago/Turabian StyleOrnella Rossetto; Cesare Montecucco. 2020. "Botulinum Neurotoxins." Encyclopedia of Molecular Pharmacology , no. : 1-9.
Tetanus and botulinum neurotoxins are the most poisonous substances known, so much so as to be considered for a possible terrorist use. At the same time, botulinum neurotoxin type A1 is successfully used to treat a variety of human syndromes characterized by hyperactive cholinergic nerve terminals. The extreme toxicity of these neurotoxins is due to their neurospecificity and to their metalloprotease activity, which results in the deadly paralysis of tetanus and botulism. Recently, many novel botulinum neurotoxins and some botulinum-like toxins have been discovered. This large number of toxins differs in terms of toxicity and biological activity, providing a potential goldmine for novel therapeutics and for new molecular tools to dissect vesicular trafficking, fusion, and exocytosis. The scattered data on toxicity present in the literature require a systematic organization to be usable by scientists and clinicians. We have assembled here the data available in the literature on the toxicity of these toxins in different animal species. The internal comparison of these data provides insights on the biological activity of these toxins.
Ornella Rossetto; Cesare Montecucco. Tables of Toxicity of Botulinum and Tetanus Neurotoxins. Toxins 2019, 11, 686 .
AMA StyleOrnella Rossetto, Cesare Montecucco. Tables of Toxicity of Botulinum and Tetanus Neurotoxins. Toxins. 2019; 11 (12):686.
Chicago/Turabian StyleOrnella Rossetto; Cesare Montecucco. 2019. "Tables of Toxicity of Botulinum and Tetanus Neurotoxins." Toxins 11, no. 12: 686.
Objective To test whether the signaling axis CXCL12α‐CXCR4 is activated upon crush/cut of the sciatic nerve and to test the activity of NUCC‐390, a new CXCR4 agonist, in promoting nerve recovery from damage. Methods The sciatic nerve was either crushed or cut. Expression and localization of CXCL12α and CXCR4 were evaluated by imaging with specific antibodies. Their functional involvement in nerve regeneration was determined by antibody‐neutralization of CXCL12α, and by the CXCR4 specific antagonist AMD3100, using as quantitative read‐out the compound muscle action potential (CMAP). NUCC‐390 activity on nerve regeneration was determined by imaging and CMAP recordings. Results CXCR4 is expressed at the injury site within the axonal compartment, whilst its ligand CXCL12α is expressed in Schwann cells. The CXCL12α‐CXCR4 axis is involved in the recovery of neurotransmission of the injured nerve. More importantly, the small molecule NUCC‐390 is a strong promoter of the functional and anatomical recovery of the nerve, by acting very similarly to CXCL12α. This pharmacological action is due to the capability of NUCC‐390 to foster elongation of motor neuron axons both in vitro and in vivo. Interpretation Imaging and electrophysiological data provide novel and compelling evidence that the CXCL12α‐CXCR4 axis is involved in sciatic nerve repair after crush/cut. This makes NUCC‐390 a strong candidate molecule to stimulate nerve repair by promoting axonal elongation. We propose this molecule to be tested in other models of neuronal damage, to lay the basis for clinical trials on the efficacy of NUCC‐390 in peripheral nerve repair in humans.
Giulia Zanetti; Samuele Negro; Aram Megighian; Andrea Mattarei; Florigio Lista; Silvia Fillo; Michela Rigoni; Marco Pirazzini; Cesare Montecucco. A CXCR4 receptor agonist strongly stimulates axonal regeneration after damage. Annals of Clinical and Translational Neurology 2019, 6, 2395 -2402.
AMA StyleGiulia Zanetti, Samuele Negro, Aram Megighian, Andrea Mattarei, Florigio Lista, Silvia Fillo, Michela Rigoni, Marco Pirazzini, Cesare Montecucco. A CXCR4 receptor agonist strongly stimulates axonal regeneration after damage. Annals of Clinical and Translational Neurology. 2019; 6 (12):2395-2402.
Chicago/Turabian StyleGiulia Zanetti; Samuele Negro; Aram Megighian; Andrea Mattarei; Florigio Lista; Silvia Fillo; Michela Rigoni; Marco Pirazzini; Cesare Montecucco. 2019. "A CXCR4 receptor agonist strongly stimulates axonal regeneration after damage." Annals of Clinical and Translational Neurology 6, no. 12: 2395-2402.
The activation of the G-protein coupled receptor CXCR4 by its ligand CXCL12α is involved in a large variety of physiological and pathological processes, including the growth of B cells precursors and of motor axons, autoimmune diseases, stem cell migration, inflammation, and several neurodegenerative conditions. Recently, we demonstrated that CXCL12α potently stimulates the functional recovery of damaged neuromuscular junctions via interaction with CXCR4. This result prompted us to test the neuroregeneration activity of small molecules acting as CXCR4 agonists, endowed with better pharmacokinetics with respect to the natural ligand. We focused on NUCC-390, recently shown to activate CXCR4 in a cellular system. We designed a novel and convenient chemical synthesis of NUCC-390, which is reported here. NUCC-390 was tested for its capability to induce the regeneration of motor axon terminals completely degenerated by the presynaptic neurotoxin α-Latrotoxin. NUCC-390 was found to strongly promote the functional recovery of the neuromuscular junction, as assayed by electrophysiology and imaging. This action is CXCR4 dependent, as it is completely prevented by AMD3100, a well-characterized CXCR4 antagonist. These data make NUCC-390 a strong candidate to be tested in human therapy to promote nerve recovery of function after different forms of neurodegeneration.
Samuele Negro; Giulia Zanetti; Andrea Mattarei; Alice Valentini; Aram Megighian; Giulia Tombesi; Alessandro Zugno; Valentina Dianin; Marco Pirazzini; Silvia Fillo; Florigio Lista; Michela Rigoni; Cesare Montecucco. An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals. Cells 2019, 8, 1183 .
AMA StyleSamuele Negro, Giulia Zanetti, Andrea Mattarei, Alice Valentini, Aram Megighian, Giulia Tombesi, Alessandro Zugno, Valentina Dianin, Marco Pirazzini, Silvia Fillo, Florigio Lista, Michela Rigoni, Cesare Montecucco. An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals. Cells. 2019; 8 (10):1183.
Chicago/Turabian StyleSamuele Negro; Giulia Zanetti; Andrea Mattarei; Alice Valentini; Aram Megighian; Giulia Tombesi; Alessandro Zugno; Valentina Dianin; Marco Pirazzini; Silvia Fillo; Florigio Lista; Michela Rigoni; Cesare Montecucco. 2019. "An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals." Cells 8, no. 10: 1183.
A large number of bacterial toxins consist of active and cell binding protomers linked by an inter‐chain disulfide bridge. The largest family of such disulfide bridged exotoxins is that of the Clostridial neurotoxins that consist of two chains and comprise the tetanus neurotoxins (TeNT) causing tetanus and the botulinum neurotoxins (BoNT) causing botulism. Reduction of the interchain disulfide abolishes toxicity and we discuss the experiments that revealed the role of this structural element in neuronal intoxication. The experiments that led to the identification of the redox couple Thioredoxin Reductase‐Thioredoxin (TrxR‐Trx) as the responsible for reduction of this disulfide occurring on the cytosolic surface of synaptic vesicles are reviewed. We then discuss the very relevant finding that drugs that inhibit TrxR‐Trx also prevent botulism. On this basis, we propose that Ebselen and PX‐12, two TrxR‐Trx specific drugs previously used in clinical trials in humans, satisfy all the requirements for clinical tests to be performed to evaluate their capacity to effectively counteract human and animal botulism arising from intestinal toxemias such as infant botulism.
Ornella Rossetto; Marco Pirazzini; Florigio Lista; Cesare Montecucco. The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs. Cellular Microbiology 2019, 21, e13037 .
AMA StyleOrnella Rossetto, Marco Pirazzini, Florigio Lista, Cesare Montecucco. The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs. Cellular Microbiology. 2019; 21 (11):e13037.
Chicago/Turabian StyleOrnella Rossetto; Marco Pirazzini; Florigio Lista; Cesare Montecucco. 2019. "The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs." Cellular Microbiology 21, no. 11: e13037.
Botulinum neurotoxin serotypes A and B are successfully used to treat a variety of human diseases characterized by hyperactive peripheral nerve terminals. However, a number of patients are primary resistant to these pharmaceuticals, without having antitoxin‐neutralizing antibodies. A straightforward explanation of this phenomenon posits that mutations of the toxin sites of interaction with their receptors or protein substrates prevent their neuroparalytic action. After a careful investigation of available human genomic databases, we conclude that it is very unlikely that humans are resistant to these two therapeutic neurotoxins because of mutations that would affect their binding or intracellular proteolytic actions.
Marco Pirazzini; Stefan Carle; Holger Barth; Ornella Rossetto; Cesare Montecucco. Primary resistance of human patients to botulinum neurotoxins A and B. Annals of Clinical and Translational Neurology 2018, 5, 971 -975.
AMA StyleMarco Pirazzini, Stefan Carle, Holger Barth, Ornella Rossetto, Cesare Montecucco. Primary resistance of human patients to botulinum neurotoxins A and B. Annals of Clinical and Translational Neurology. 2018; 5 (8):971-975.
Chicago/Turabian StyleMarco Pirazzini; Stefan Carle; Holger Barth; Ornella Rossetto; Cesare Montecucco. 2018. "Primary resistance of human patients to botulinum neurotoxins A and B." Annals of Clinical and Translational Neurology 5, no. 8: 971-975.
The presence of botulinum neurotoxin-producing Clostridia (BPC) in food sources is a public health concern. In favorable environmental conditions, BPC can produce botulinum neurotoxins (BoNTs) outside or inside the vertebrate host, leading to intoxications or toxico-infectious forms of botulism, respectively. BPC in food are almost invariably detected either by PCR protocols targeted at the known neurotoxin-encoding genes, or by the mouse test to assay for the presence of BoNTs in the supernatants of enrichment broths inoculated with the tested food sample. The sample is considered positive for BPC when the supernatant contains toxic substances that are lethal to mice, heat-labile and neutralized in vivo by appropriate polyclonal antibodies raised against purified BoNTs of different serotypes. Here, we report the detection in a food sample of a Clostridium tetani strain that produces tetanus neurotoxins (TeNTs) with the above-mentioned characteristics: lethal for mice, heat-labile and neutralized by botulinum antitoxin type B. Notably, neutralization occurred with two different commercially available type B antitoxins, but not with type A, C, D, E and F antitoxins. Although TeNT and BoNT fold very similarly, evidence that antitoxin B antiserum can neutralize the neurotoxic effect of TeNT in vivo has not been documented before. The presence of C. tetani strains in food can produce misleading results in BPC detection using the mouse test.
Luca Bano; Elena Tonon; Ilenia Drigo; Marco Pirazzini; Angela Guolo; Giovanni Farina; Fabrizio Agnoletti; Cesare Montecucco. Detection of Clostridium tetani Neurotoxins Inhibited In Vivo by Botulinum Antitoxin B: Potential for Misleading Mouse Test Results in Food Controls. Toxins 2018, 10, 248 .
AMA StyleLuca Bano, Elena Tonon, Ilenia Drigo, Marco Pirazzini, Angela Guolo, Giovanni Farina, Fabrizio Agnoletti, Cesare Montecucco. Detection of Clostridium tetani Neurotoxins Inhibited In Vivo by Botulinum Antitoxin B: Potential for Misleading Mouse Test Results in Food Controls. Toxins. 2018; 10 (6):248.
Chicago/Turabian StyleLuca Bano; Elena Tonon; Ilenia Drigo; Marco Pirazzini; Angela Guolo; Giovanni Farina; Fabrizio Agnoletti; Cesare Montecucco. 2018. "Detection of Clostridium tetani Neurotoxins Inhibited In Vivo by Botulinum Antitoxin B: Potential for Misleading Mouse Test Results in Food Controls." Toxins 10, no. 6: 248.
Ornella Rossetto; Cesare Montecucco; Dirk Dressler; Eckart Altenmüller; Joachim K. Krauss. Molecular Mechanisms of Botulinum Toxin. Treatment of Dystonia 2018, 102 -105.
AMA StyleOrnella Rossetto, Cesare Montecucco, Dirk Dressler, Eckart Altenmüller, Joachim K. Krauss. Molecular Mechanisms of Botulinum Toxin. Treatment of Dystonia. 2018; ():102-105.
Chicago/Turabian StyleOrnella Rossetto; Cesare Montecucco; Dirk Dressler; Eckart Altenmüller; Joachim K. Krauss. 2018. "Molecular Mechanisms of Botulinum Toxin." Treatment of Dystonia , no. : 102-105.
Botulinum (BoNTs) and tetanus (TeNT) neurotoxins are the most toxic substances known and form the growing family of Clostridial neurotoxins (CNT), the etiologic agents of botulism and tetanus. CNT are composed of a metalloprotease light chain (L), linked via a disulfide bond to a heavy chain (H). H mediates the binding to nerve terminals and the membrane translocation of L into the cytosol, where its substrates, the three SNARE proteins, are localized. L translocation is accompanied by unfolding and, once delivered on the cytosolic side of the endosome membrane, it has to be reduced and reacquire the native fold to be active. The Thioredoxin-Thioredoxin Reductase system (Trx-TrxR) specifically reduces the interchain disulfide bond while the cytosolic chaperone protein Hsp90 mediates L refolding. Both steps are essential for CNT activity and their inhibition efficiently blocks the neurotoxicity in cultured neurons and mice. Trx and its reductase physically interact with Hsp90 and are loosely bound to the cytosolic side of synaptic vesicles, the organelle exploited by CNT to enter nerve terminals and wherefrom L is translocated into the cytosol. Therefore, Trx, TrxR and Hsp90 orchestrate a chaperone-redox molecular machinery that enables the catalytic activity of the L inside nerve terminals. Given the fundamental role of L reduction and refolding, this machinery represents a rational target for the development of mechanism-based antitoxins.
Marco Pirazzini; Domenico Azarnia Tehran; Giulia Zanetti; Ornella Rossetto; Cesare Montecucco. Hsp90 and Thioredoxin-Thioredoxin Reductase enable the catalytic activity of Clostridial neurotoxins inside nerve terminals. Toxicon 2018, 147, 32 -37.
AMA StyleMarco Pirazzini, Domenico Azarnia Tehran, Giulia Zanetti, Ornella Rossetto, Cesare Montecucco. Hsp90 and Thioredoxin-Thioredoxin Reductase enable the catalytic activity of Clostridial neurotoxins inside nerve terminals. Toxicon. 2018; 147 ():32-37.
Chicago/Turabian StyleMarco Pirazzini; Domenico Azarnia Tehran; Giulia Zanetti; Ornella Rossetto; Cesare Montecucco. 2018. "Hsp90 and Thioredoxin-Thioredoxin Reductase enable the catalytic activity of Clostridial neurotoxins inside nerve terminals." Toxicon 147, no. : 32-37.
Cambridge Core - Neurology and Clinical Neuroscience - Treatment of Dystonia - edited by Dirk Dressler
Stanley Fahn; Alberto Albanese; Stefania Lalli; Bettina Balint; Roberto Erro; Kailash P. Bhatia; Peter Kaňovský; Bulent Elibol; Gul Yalcin Cakmakli; Hyder A. Jinnah; Ellen J. Hess; Scott A. Norris; Joel S. Perlmutter; Jung E. Park; Sophie Cho; Mark Hallett; Marta Maltese; Paola Imbriani; Antonio Pisani; Aloysius Domingo; Christine Klein; Thomas T. Warner; Daniela Hansen; Ellen B. Penney; Elan D. Louis; Karen Frei; Daniel Truong; Marjan Jahanshahi; Cynthia L. Comella; Glenn T. Stebbins; Sophie Cleanthous; Stefan J. Cano; Fereshte Adib Saberi; Marianne King; Frank Erbguth; Hansjörg Bäzner; Christian Riederer; Andy Pickett; Ornella Rossetto; Cesare Montecucco. Treatment of Dystonia. Treatment of Dystonia 2018, 1 .
AMA StyleStanley Fahn, Alberto Albanese, Stefania Lalli, Bettina Balint, Roberto Erro, Kailash P. Bhatia, Peter Kaňovský, Bulent Elibol, Gul Yalcin Cakmakli, Hyder A. Jinnah, Ellen J. Hess, Scott A. Norris, Joel S. Perlmutter, Jung E. Park, Sophie Cho, Mark Hallett, Marta Maltese, Paola Imbriani, Antonio Pisani, Aloysius Domingo, Christine Klein, Thomas T. Warner, Daniela Hansen, Ellen B. Penney, Elan D. Louis, Karen Frei, Daniel Truong, Marjan Jahanshahi, Cynthia L. Comella, Glenn T. Stebbins, Sophie Cleanthous, Stefan J. Cano, Fereshte Adib Saberi, Marianne King, Frank Erbguth, Hansjörg Bäzner, Christian Riederer, Andy Pickett, Ornella Rossetto, Cesare Montecucco. Treatment of Dystonia. Treatment of Dystonia. 2018; ():1.
Chicago/Turabian StyleStanley Fahn; Alberto Albanese; Stefania Lalli; Bettina Balint; Roberto Erro; Kailash P. Bhatia; Peter Kaňovský; Bulent Elibol; Gul Yalcin Cakmakli; Hyder A. Jinnah; Ellen J. Hess; Scott A. Norris; Joel S. Perlmutter; Jung E. Park; Sophie Cho; Mark Hallett; Marta Maltese; Paola Imbriani; Antonio Pisani; Aloysius Domingo; Christine Klein; Thomas T. Warner; Daniela Hansen; Ellen B. Penney; Elan D. Louis; Karen Frei; Daniel Truong; Marjan Jahanshahi; Cynthia L. Comella; Glenn T. Stebbins; Sophie Cleanthous; Stefan J. Cano; Fereshte Adib Saberi; Marianne King; Frank Erbguth; Hansjörg Bäzner; Christian Riederer; Andy Pickett; Ornella Rossetto; Cesare Montecucco. 2018. "Treatment of Dystonia." Treatment of Dystonia , no. : 1.
Schwann cells are key players in neuro-regeneration: They sense “alarm” signals released by degenerating nerve terminals and differentiate toward a proregenerative phenotype, with phagocytosis of nerve debris and nerve guidance. At the murine neuromuscular junction, hydrogen peroxide (H2O2) is a key signal of Schwann cells’ activation in response to a variety of nerve injuries. Here we report that Schwann cells exposed to low doses of H2O2 rewire the expression of several RNAs at both transcriptional and translational levels. Among the genes positively regulated at both levels, we identified an enriched cluster involved in cytoskeleton remodeling and cell migration, with the Annexin (Anxa) proteins being the most represented family. We show that both Annexin A2 (Anxa2) transcript and protein accumulate at the tips of long pseudopods that Schwann cells extend upon H2O2 exposure. Interestingly, Schwann cells reply to this signal and to nerve injury by locally translating Anxa2 in pseudopods, and undergo an extensive cytoskeleton remodeling. Our results show that, similarly to neurons, Schwann cells take advantage of local protein synthesis to change shape and move toward damaged axonal terminals to facilitate axonal regeneration.
Samuele Negro; Marco Stazi; Marta Marchioretto; Toma Tebaldi; Umberto Rodella; Elisa Duregotti; Volker Gerke; Alessandro Quattrone; Cesare Montecucco; Michela Rigoni; Gabriella Viero. Hydrogen peroxide is a neuronal alarmin that triggers specific RNAs, local translation of Annexin A2, and cytoskeletal remodeling in Schwann cells. RNA 2018, 24, 915 -925.
AMA StyleSamuele Negro, Marco Stazi, Marta Marchioretto, Toma Tebaldi, Umberto Rodella, Elisa Duregotti, Volker Gerke, Alessandro Quattrone, Cesare Montecucco, Michela Rigoni, Gabriella Viero. Hydrogen peroxide is a neuronal alarmin that triggers specific RNAs, local translation of Annexin A2, and cytoskeletal remodeling in Schwann cells. RNA. 2018; 24 (7):915-925.
Chicago/Turabian StyleSamuele Negro; Marco Stazi; Marta Marchioretto; Toma Tebaldi; Umberto Rodella; Elisa Duregotti; Volker Gerke; Alessandro Quattrone; Cesare Montecucco; Michela Rigoni; Gabriella Viero. 2018. "Hydrogen peroxide is a neuronal alarmin that triggers specific RNAs, local translation of Annexin A2, and cytoskeletal remodeling in Schwann cells." RNA 24, no. 7: 915-925.
The Genome Aggregation Database presently contains >120,000 human genomes. We searched in this database for the presence of mutations at the sites of tetanus (TeNT) and botulinum neurotoxins (BoNTs) cleavages of the three SNARE proteins: VAMP, SNAP-25 and Syntaxin. These mutations could account for some of the BoNT/A resistant patients. At the same time, this approach was aimed at testing the possibility that TeNT and BoNT may have acted as selective agents in the development of resistance to tetanus or botulism. We found that mutations of the SNARE proteins are very rare and concentrated outside the SNARE motif required for the formation of the SNARE complex involved in neuroexocytosis. No changes were found at the BoNT cleavage sites of VAMP and syntaxins and only one very rare mutation was found in the essential C-terminus region of SNAP-25, where Arg198 was replaced with a Cys residue. This is the P1’ cleavage site for BoNT/A and the P1 cleavage site for BoNT/C. We found that the Arg198Cys mutation renders SNAP-25 resistant to BoNT/A. Nonetheless, its low frequency (1.8 × 10−5) indicates that mutations of SNAP-25 at the BoNT/A cleavage site are unlikely to account for the existence of BoNT/A resistant patients. More in general, the present findings indicate that tetanus and botulinum neurotoxins have not acted as selective agents during human evolution as it appears to have been the case for tetanus in rats and chicken.
Stefan Carle; Marco Pirazzini; Ornella Rossetto; Holger Barth; Cesare Montecucco. High Conservation of Tetanus and Botulinum Neurotoxins Cleavage Sites on Human SNARE Proteins Suggests That These Pathogens Exerted Little or No Evolutionary Pressure on Humans. Toxins 2017, 9, 404 .
AMA StyleStefan Carle, Marco Pirazzini, Ornella Rossetto, Holger Barth, Cesare Montecucco. High Conservation of Tetanus and Botulinum Neurotoxins Cleavage Sites on Human SNARE Proteins Suggests That These Pathogens Exerted Little or No Evolutionary Pressure on Humans. Toxins. 2017; 9 (12):404.
Chicago/Turabian StyleStefan Carle; Marco Pirazzini; Ornella Rossetto; Holger Barth; Cesare Montecucco. 2017. "High Conservation of Tetanus and Botulinum Neurotoxins Cleavage Sites on Human SNARE Proteins Suggests That These Pathogens Exerted Little or No Evolutionary Pressure on Humans." Toxins 9, no. 12: 404.
Animal botulism is primarily due to botulinum neurotoxin (BoNT) types C, D or their chimeric variants C/D or D/C, produced by Clostridium botulinum group III, which appears to include the genetically indistinguishable Clostridium haemolyticum and Clostridium novyi. In the present study, we used matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI TOF MS) to identify and characterize 81 BoNT-producing Clostridia isolated in 47 episodes of animal botulism. The instrument's default database, containing no entries for Clostridium botulinum, permitted reliable identification of 26 strains at the genus level. Although supplementation of the database with reference strains enhanced the instrument's ability to identify the neurotoxic strains at the genus level, resolution was not sufficient to recognize field strains at species level. Characterization by MALDI TOF confirmed the well-documented phenotypic and genetic differences between Clostridium botulinum strains of serotypes normally implicated in human botulism (A, B, E, F) and other Clostridium species able to produce BoNTs type C and D. The chimeric and non-chimeric field strains grouped separately. In particular, very low similarity was found between two non-chimeric type C field strains isolated in the same outbreak and the other field strains. This difference was comparable with the differences among the various Clostridia species included in the study. Characterization by MALDI TOF confirmed that BoNT-producing Clostridia isolated from animals are closely related and indistinguishable at the species level from Clostridium haemolyticum and Clostridium novyi reference strains. On the contrary, there seem to be substantial differences among chimeric and some non-chimeric type C strains.
Luca Bano; Ilenia Drigo; Elena Tonon; Simone Pascoletti; Cinzia Puiatti; Fabrizio Anniballi; Bruna Auricchio; Florigio Lista; Cesare Montecucco; Fabrizio Agnoletti. Identification and characterization of C lostridium botulinum group III field strains by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS). Anaerobe 2017, 48, 126 -134.
AMA StyleLuca Bano, Ilenia Drigo, Elena Tonon, Simone Pascoletti, Cinzia Puiatti, Fabrizio Anniballi, Bruna Auricchio, Florigio Lista, Cesare Montecucco, Fabrizio Agnoletti. Identification and characterization of C lostridium botulinum group III field strains by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS). Anaerobe. 2017; 48 ():126-134.
Chicago/Turabian StyleLuca Bano; Ilenia Drigo; Elena Tonon; Simone Pascoletti; Cinzia Puiatti; Fabrizio Anniballi; Bruna Auricchio; Florigio Lista; Cesare Montecucco; Fabrizio Agnoletti. 2017. "Identification and characterization of C lostridium botulinum group III field strains by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS)." Anaerobe 48, no. : 126-134.