The Clostridial genus comprises a great variety of different bacteria, but few neurotoxigenic strains. Some of these produce and release the most potent toxins known, namely Tetanus Neurotoxin (TeNT) and Botulinum Neurotoxins (BoNTs), which cause the neuroparalytic syndromes tetanus and botulism, respectively. Tetanus is characterized by the contemporary and uncontrolled hypercontraction of all skeletal muscles, named spastic paralysis. This is due to the proteolytic activity of TeNT in GABAergic and glycinergic inhibitory interneurons in the Central Nervous System (CNS). Indeed, the cleavage of the vesicle-associated protein VAMP leads to the inhibition of vesicle fusion with the pre-synaptic plasma membrane and the consequent blockade of neurotransmission. This proteolytic activity results in the inhibition of the interneurons-dependent coordination of antagonist muscles contraction. In contrast, botulism is characterized by flaccid paralysis of skeletal muscles, due to the cleavage of proteins SNAP25, Syntaxin or VAMP in cholinergic motoneurons at the level of Neuromuscular Junctions (NMJs), all proteins required for vesicles fusion. In both diseases, death comes by respiratory failure. These syndromes are successfully kept under control in economically developed countries, but they still represent a major health threaten in poor countries, especially tetanus. The knowledge about these toxins are extensive, such that Botulinum Neurotoxin is now widely used as a medical and cosmetic tool. Nevertheless, several aspects remain to be clarified, both for tetanus and for botulism. Among the different forms of tetanus, we focused on the most aggressive one, namely Cephalic Tetanus (CT). CT is characterised by an initial facial, flaccid paralysis that delays the correct diagnosis, and by a rapid respiratory failure, which appears even in absence of evident signs of tetanus. In my first project, I focus on studying the molecular pathogenesis underlying these two aspects of CT by analysing peripheral and central activity of TeNT. The second project I developed during my PhD is about foodborne botulism. The natural route for BoNT to entry into the host body is through the digestive system, after the ingestion of foods contaminated with the preformed toxin. Nevertheless, the literature about the interaction of the toxin with the gut is scarce, and focuses mainly on the mechanism of entry rather than the pathological effects of BoNTs on this complex and fascinating organ, which counts with a wide neuronal network called Enteric Nervous System (ENS). Therefore, I reproduced a model of foodborne botulism by gavage-feeding mice with BoNT complex, to focus then on the effects of the intoxication on enteric physiology.

The Clostridial genus comprises a great variety of different bacteria, but few neurotoxigenic strains. Some of these produce and release the most potent toxins known, namely Tetanus Neurotoxin (TeNT) and Botulinum Neurotoxins (BoNTs), which cause the neuroparalytic syndromes tetanus and botulism, respectively. Tetanus is characterized by the contemporary and uncontrolled hypercontraction of all skeletal muscles, named spastic paralysis. This is due to the proteolytic activity of TeNT in GABAergic and glycinergic inhibitory interneurons in the Central Nervous System (CNS). Indeed, the cleavage of the vesicle-associated protein VAMP leads to the inhibition of vesicle fusion with the pre-synaptic plasma membrane and the consequent blockade of neurotransmission. This proteolytic activity results in the inhibition of the interneurons-dependent coordination of antagonist muscles contraction. In contrast, botulism is characterized by flaccid paralysis of skeletal muscles, due to the cleavage of proteins SNAP25, Syntaxin or VAMP in cholinergic motoneurons at the level of Neuromuscular Junctions (NMJs), all proteins required for vesicles fusion. In both diseases, death comes by respiratory failure. These syndromes are successfully kept under control in economically developed countries, but they still represent a major health threaten in poor countries, especially tetanus. The knowledge about these toxins are extensive, such that Botulinum Neurotoxin is now widely used as a medical and cosmetic tool. Nevertheless, several aspects remain to be clarified, both for tetanus and for botulism. Among the different forms of tetanus, we focused on the most aggressive one, namely Cephalic Tetanus (CT). CT is characterised by an initial facial, flaccid paralysis that delays the correct diagnosis, and by a rapid respiratory failure, which appears even in absence of evident signs of tetanus. In my first project, I focus on studying the molecular pathogenesis underlying these two aspects of CT by analysing peripheral and central activity of TeNT. The second project I developed during my PhD is about foodborne botulism. The natural route for BoNT to entry into the host body is through the digestive system, after the ingestion of foods contaminated with the preformed toxin. Nevertheless, the literature about the interaction of the toxin with the gut is scarce, and focuses mainly on the mechanism of entry rather than the pathological effects of BoNTs on this complex and fascinating organ, which counts with a wide neuronal network called Enteric Nervous System (ENS). Therefore, I reproduced a model of foodborne botulism by gavage-feeding mice with BoNT complex, to focus then on the effects of the intoxication on enteric physiology.

Unravelling the dark side of Clostridial neurotoxins: a deepening into Cephalic Tetanus and Foodborne Botulism

FABRIS, FEDERICO
2023

Abstract

The Clostridial genus comprises a great variety of different bacteria, but few neurotoxigenic strains. Some of these produce and release the most potent toxins known, namely Tetanus Neurotoxin (TeNT) and Botulinum Neurotoxins (BoNTs), which cause the neuroparalytic syndromes tetanus and botulism, respectively. Tetanus is characterized by the contemporary and uncontrolled hypercontraction of all skeletal muscles, named spastic paralysis. This is due to the proteolytic activity of TeNT in GABAergic and glycinergic inhibitory interneurons in the Central Nervous System (CNS). Indeed, the cleavage of the vesicle-associated protein VAMP leads to the inhibition of vesicle fusion with the pre-synaptic plasma membrane and the consequent blockade of neurotransmission. This proteolytic activity results in the inhibition of the interneurons-dependent coordination of antagonist muscles contraction. In contrast, botulism is characterized by flaccid paralysis of skeletal muscles, due to the cleavage of proteins SNAP25, Syntaxin or VAMP in cholinergic motoneurons at the level of Neuromuscular Junctions (NMJs), all proteins required for vesicles fusion. In both diseases, death comes by respiratory failure. These syndromes are successfully kept under control in economically developed countries, but they still represent a major health threaten in poor countries, especially tetanus. The knowledge about these toxins are extensive, such that Botulinum Neurotoxin is now widely used as a medical and cosmetic tool. Nevertheless, several aspects remain to be clarified, both for tetanus and for botulism. Among the different forms of tetanus, we focused on the most aggressive one, namely Cephalic Tetanus (CT). CT is characterised by an initial facial, flaccid paralysis that delays the correct diagnosis, and by a rapid respiratory failure, which appears even in absence of evident signs of tetanus. In my first project, I focus on studying the molecular pathogenesis underlying these two aspects of CT by analysing peripheral and central activity of TeNT. The second project I developed during my PhD is about foodborne botulism. The natural route for BoNT to entry into the host body is through the digestive system, after the ingestion of foods contaminated with the preformed toxin. Nevertheless, the literature about the interaction of the toxin with the gut is scarce, and focuses mainly on the mechanism of entry rather than the pathological effects of BoNTs on this complex and fascinating organ, which counts with a wide neuronal network called Enteric Nervous System (ENS). Therefore, I reproduced a model of foodborne botulism by gavage-feeding mice with BoNT complex, to focus then on the effects of the intoxication on enteric physiology.
7-giu-2023
Inglese
The Clostridial genus comprises a great variety of different bacteria, but few neurotoxigenic strains. Some of these produce and release the most potent toxins known, namely Tetanus Neurotoxin (TeNT) and Botulinum Neurotoxins (BoNTs), which cause the neuroparalytic syndromes tetanus and botulism, respectively. Tetanus is characterized by the contemporary and uncontrolled hypercontraction of all skeletal muscles, named spastic paralysis. This is due to the proteolytic activity of TeNT in GABAergic and glycinergic inhibitory interneurons in the Central Nervous System (CNS). Indeed, the cleavage of the vesicle-associated protein VAMP leads to the inhibition of vesicle fusion with the pre-synaptic plasma membrane and the consequent blockade of neurotransmission. This proteolytic activity results in the inhibition of the interneurons-dependent coordination of antagonist muscles contraction. In contrast, botulism is characterized by flaccid paralysis of skeletal muscles, due to the cleavage of proteins SNAP25, Syntaxin or VAMP in cholinergic motoneurons at the level of Neuromuscular Junctions (NMJs), all proteins required for vesicles fusion. In both diseases, death comes by respiratory failure. These syndromes are successfully kept under control in economically developed countries, but they still represent a major health threaten in poor countries, especially tetanus. The knowledge about these toxins are extensive, such that Botulinum Neurotoxin is now widely used as a medical and cosmetic tool. Nevertheless, several aspects remain to be clarified, both for tetanus and for botulism. Among the different forms of tetanus, we focused on the most aggressive one, namely Cephalic Tetanus (CT). CT is characterised by an initial facial, flaccid paralysis that delays the correct diagnosis, and by a rapid respiratory failure, which appears even in absence of evident signs of tetanus. In my first project, I focus on studying the molecular pathogenesis underlying these two aspects of CT by analysing peripheral and central activity of TeNT. The second project I developed during my PhD is about foodborne botulism. The natural route for BoNT to entry into the host body is through the digestive system, after the ingestion of foods contaminated with the preformed toxin. Nevertheless, the literature about the interaction of the toxin with the gut is scarce, and focuses mainly on the mechanism of entry rather than the pathological effects of BoNTs on this complex and fascinating organ, which counts with a wide neuronal network called Enteric Nervous System (ENS). Therefore, I reproduced a model of foodborne botulism by gavage-feeding mice with BoNT complex, to focus then on the effects of the intoxication on enteric physiology.
ROSSETTO, ORNELLA
Università degli studi di Padova
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14242/95154
Il codice NBN di questa tesi è URN:NBN:IT:UNIPD-95154