Speaker: Cesare Montecucco
Member of Accademia dei Lincei, Associated Scientist at the CNR Institute of Neuroscience, Professor Emeritus at the University of Padova, Italy
Title:
Botulinum neurotoxins affect the enteric nervous system and intestinal defence reactions
Abstract:
Intestinal Botulism is a rare but potentially fatal disease caused by neurotoxins (BoNTs) released in the intestine by anaerobic bacteria of the genus Clostridium. Botulism outbreaks typically involve many people who show symptoms of varying severity depending on the amount of BoNT ingested with contaminated food. BoNTs ( > 50 different subtypes) cross the intestinal barrier and diffuse in the whole organism reaching and binding peripheral presynaptic nerve terminals. They enter the nerve cytosol and cleave one or more of the three SNARE proteins: VAMP, SNAP-25 and syntaxin, thereby blocking neuroexocytosis of neurotransmitters and hormones. This specific block causes a flaccid paralysis and autonomic symptoms that lead to death by respiratory and cardiac deficits.
Little attention has been paid so far to the action of BoNTs on the enteric nervous system (ENS) that regulates intestinal physiology. We have recently shown that BoNT/A and BoNT/B, which are responsible for most cases of human botulism, enter cholinergic neurons of murine ENS and cleave SNARE proteins. This biochemical lesion was observed even with very low doses of BoNT/A and BoNT/B that do not cause any botulism symptom. However, the impaired release of acetylcholine was found to lower the intestinal defense against the invasion of the mucosa and spread of two prototypic intestinal pathogenic bacteria: Salmonella thyphimurium and Shigella flexneri, that act similarly in mice and humans. One specific defense alteration caused by BoNTs was found to be the reduction of the mucous layer that covers and protects the intestinal polarized cell layer.
These findings indicate that intoxications with very low amount of BoNTs, that are not noticed because lack of overt symptoms, may be at the origin of dangerous bacterial infections. It follows that all people involved in botulism outbreaks, even those not exhibiting any botulism symptom, should be treated with antibiotics to prevent intestinal infections.
Biosketch
He has studied the molecular and cellular pathogenesis of diseases caused by toxin-producing pathogenic bacteria (anthrax, botulism, tetanus, Helicobacter pylori) and by poisonous snakes and insects. He has carried out research in the Universities of Cambridge, Utrecht, and Costa Rica, the Institut Pasteur of Paris and the EMBL of Heidelberg.
Currently, he works at the discovery of factors and signals involved in the regeneration of the neuromuscular junction after damage caused by toxins, autoantibodies and mechanical traumas. He also aims at identifying molecules that can improve peripheral neuroregeneration.
Major discoveries: a) the metalloprotease activity of the neurotoxins responsible for tetanus, botulism and of the anthrax lethal factor, b) their proteins targets (SNAREs) including sites of cleavage and mechanism of specific recognition, c) the mechanism of action of two major virulence factors of H. pylori: VacA and NapA, included in the Novartis anti Hp vaccine, d) the mechanism of action of the snake presynaptic PLA2 neurotoxins, d) the intercellular signalling axis CXCL12 – CXCR4 and melatonin – melatonin receptors control regeneration of the neuromuscular junction.
He has received several scientific prizes and is member of the following Academies: Lincei, Leopoldina, EMBO, Academia Europaea, IVSLA and both the European and the American Academies of Microbiology.
He has published 273 experimental papers + 94 reviews and opinion papers + 3 books. > 45.000 references, H index 111.
Interview: https://www.mdpi.com/2072-6651/10/8/307/htm