title: Translocation and dissemination to target neurons of botulinum neurotoxin type B in the mouse intestinal wall.
abstract: Botulinum neurotoxins (BoNTs) are responsible for severe flaccid paralysis (botulism), which in most cases enter the organism via the digestive tract and then disseminate into the blood or lymph circulation to target autonomic and motor nerve endings. The passage way of BoNTs alone or in complex forms with associated nontoxic proteins through the epithelial barrier of the digestive tract still remains unclear. Here, we show using an in vivo model of mouse ligated intestinal loop that BoNT/B alone or the BoNT/B C-terminal domain of the heavy chain (HCcB), which interacts with cell surface receptors, translocates across the intestinal barrier. The BoNT/B or HCcB translocation through the intestinal barrier occurred via an endocytosis-dependent mechanism within 10-20 min, because Dynasore, a potent endocytosis inhibitor, significantly prevented BoNT/B as well as HCcB translocation. We also show that HCcB or BoNT/B specifically targets neuronal cells and neuronal extensions in the intestinal submucosa and musculosa expressing synaptotagmin, preferentially cholinergic neurons and to a lower extent other neuronal cell types, notably serotonergic neurons. Interestingly, rare intestinal epithelial cells accumulated HCcB suggesting that distinct cell types of the intestinal epithelium, still undefined, might mediate efficient translocation of BoNT/B.
authors: Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, 75724, France.
authors: Chloé
authors: C
authors: Connan
authors: Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, 75724, France.
authors: Carolina
authors: C
authors: Varela-Chavez
authors: Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, 75724, France.
authors: Christelle
authors: C
authors: Mazuet
authors: Service d'Ingénierie Moléculaire des Protéines, Laboratoire de Toxinologie Moléculaire et Biotechnologies, CEA, iBiTec-S, bâtiment 152, courrier N° 24, Gif-sur-Yvette, 91191, France.|Institut des Neurosciences Paris-Saclay, UMR 9197, CNRS, Gif-sur-Yvette, 91190, France.
authors: Jordi
authors: J
authors: Molgó
authors: Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, 75724, France.
authors: Georges Michel
authors: GM
authors: Haustant
authors: Unité de Biologie des Infections, Institut Pasteur, Paris, 75724, France.
authors: Olivier
authors: O
authors: Disson
authors: Unité de Biologie des Infections, Institut Pasteur, Paris, 75724, France.
authors: Marc
authors: M
authors: Lecuit
authors: Centre de Recherche sur l'Inflammation (CRI), UMRS 1149, Université Paris 7-Denis Diderot, site Bichat, Paris, 75018, France.
authors: Alain
authors: A
authors: Vandewalle
authors: Unité des Bactéries anaérobies et Toxines, Institut Pasteur, Paris, 75724, France.
authors: Michel R
authors: MR
authors: Popoff
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000378:metabolism*; D059329:Cholinergic Neurons / Q000378:metabolism*; D004705:Endocytosis; D004847:Epithelial Cells / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D021381:Protein Transport; D059326:Serotonergic Neurons / Q000378:metabolism; D013997:Time Factors
chemical_list: C096323:rimabotulinumtoxinB; D019274:Botulinum Toxins, Type A
keywords: botulinum neurotoxin; botulism; cholinergic neuron; endocytosis; intestinal barrier; neuron; translocation