Skip to main content
SpringerLink
Log in

Uptake of Clostridial Neurotoxins into Cells and Dissemination

  • Chapter
  • First Online:
Uptake and Trafficking of Protein Toxins

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 406))

Abstract

Clostridial neurotoxins, botulinum neurotoxins (BoNT) and tetanus neurotoxin (TeNT), are potent toxins, which are responsible for severe neurological diseases in man and animals. BoNTs induce a flaccid paralysis (botulism) by inhibiting acetylcholine release at the neuromuscular junctions, whereas TeNT causes a spastic paralysis (tetanus) by blocking the neurotransmitter release (glycine, GABA) in inhibitory interneurons within the central nervous system. Clostridial neurotoxins recognize specific receptor(s) on the target neuronal cells and enter via a receptor-mediated endocytosis. They transit through an acidic compartment which allows the translocation of the catalytic chain into the cytosol, a prerequisite step for the intracellular activity of the neurotoxins. TeNT migrates to the central nervous system by using a motor neuron as transport cell. TeNT enters a neutral pH compartment and undergoes a retrograde axonal transport to the spinal cord or brain, where the whole undissociated toxin is delivered and interacts with target neurons. Botulism most often results from ingestion of food contaminated with BoNT. Thus, BoNT passes through the intestinal epithelial barrier mainly via a transcytotic mechanism and then diffuses or is transported to the neuromuscular junctions by the lymph or blood circulation. Indeed, clostridial neurotoxins are specific neurotoxins which transit through a transport cell to gain access to the target neuron, and use distinct trafficking pathways in both cell types.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahsan CR, Hajnoczky G, Maksymowych AB, Simpson LL (2005) Visualization of binding and transcytosis of botulinum toxin by human intestinal epithelial cells. J Pharmacol Exp Ther 315:1028–1035

    Article  CAS  PubMed  Google Scholar 

  • Akaike N, Shin MC, Wakita M, Torii Y, Harakawa T, Ginnaga A, Kato K, Kaji R, Kozaki S (2013) Transsynaptic inhibition of spinal transmission by A2 botulinum toxin. J Physiol 591(4):1031–1043

    Article  CAS  PubMed  Google Scholar 

  • Al-Saleem FH, Ancharski DM, Joshi SG, Elias M, Singh A, Nasser Z, Simpson LL (2012) Analysis of the mechanisms that underlie absorption of botulinum toxin by the inhalation route. Infect Immun 80(12):4133–4142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amatsu S, Sugawara Y, Matsumura T, Kitadokoro K, Fujinaga Y (2013) Crystal structure of Clostridium botulinum whole hemagglutinin reveals a huge triskelion-shaped molecular complex. J Biol Chem 288(49):35617–35625. doi:10.1074/jbc.M35113.521179. Epub 522013 Oct 521128

  • Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M (2008) Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci 28(14):3689–3696

    Article  CAS  PubMed  Google Scholar 

  • Araye A, Goudet A, Barbier J, Pichard S, Baron B, England P, Perez J, Zinn-Justin S, Chenal A, Gillet D (2016) The translocation domain of botulinum neurotoxin a moderates the propensity of the catalytic domain to interact with membranes at acidic pH. PLoS ONE 11(4):e0153401

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arimitsu H, Sakaguchi Y, Lee JC, Ochi S, Tsukamoto K, Yamamoto Y, Ma S, Tsuji T, Oguma K (2008) Molecular properties of each subcomponent in Clostridium botulinum type B haemagglutinin complex. Microb Pathog 45(2):142–149

    Article  CAS  PubMed  Google Scholar 

  • Arndt JW, Gu J, Jaroszewski L, Schwarzenbacher R, Hanson MA, Lebeda FJ, Stevens RC (2005) The structure of the neurotoxin-associated protein HA33/A from Clostridium botulinum suggests a reoccurring beta-trefoil fold in the progenitor toxin complex. J Mol Biol 346(4):1083–1093

    Article  CAS  PubMed  Google Scholar 

  • Bagramyan K, Kaplan BE, Cheng LW, Strotmeier J, Rummel A, Kalkum M (2013) Substrates and controls for the quantitative detection of active botulinum neurotoxin in protease-containing samples. Anal Chem 85(11):5569–5576. doi:10.1021/ac4008418. Epub 4002013 May 4008422

  • Barash JR, Arnon SS (2014) A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins. J Infect Dis 209(2):183–191. doi:10.1093/infdis/jit1449. Epub 2013 Oct 1097

  • Beard M (2014) Translocation, entry into the cell. In: Foster KA (ed) Molecular aspects of botulinum neurotoxins. Springer, pp 151–170

    Google Scholar 

  • Benefield DA, Dessain SK, Shine N, Ohi MD, Lacy DB (2013) Molecular assembly of botulinum neurotoxin progenitor complexes. Proc Natl Acad Sci U S A. 110(14):5630–5635. doi:10.1073/pnas.1222139110. Epub 1222132013 Mar 1222139118

  • Benoit RM, Frey D, Hilbert M, Kevenaar JT, Wieser MM, Stirnimann CU, McMillan D, Ceska T, Lebon F, Jaussi R, Steinmetz MO, Schertler GF, Hoogenraad CC, Capitani G, Kammerer RA (2014) Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A. Nature 505(7481):108–111. doi:10.1038/nature12732. Epub 12013 Nov 12717

  • Bens M, Bogdanova A, Cluzeaud F, Miquerol L, Kerneis S, Kraehenbuhl JP, Kahn A, Pringault E, Vandewalle A (1996) Transimmortalized mouse intestinal cells (m-ICc12) that maintain a crypt phenotype. Am J Physiol 270(6 Pt 1):C1666–C1674

    CAS  PubMed  Google Scholar 

  • Bercsenyi K, Giribaldi F, Schiavo G (2013) The elusive compass of clostridial neurotoxins: deciding when and where to go? Curr Top Microbiol Immunol 364:91–113

    CAS  PubMed  Google Scholar 

  • Bercsenyi K, Schmieg N, Bryson JB, Wallace M, Caccin P, Golding M, Zanotti G, Greensmith L, Nischt R, Schiavo G (2014) Tetanus toxin entry. Nidogens are therapeutic targets for the prevention of tetanus. Science 346(6213):1118–1123.

    Article  CAS  PubMed  Google Scholar 

  • Berntsson RP, Peng L, Dong M, Stenmark P (2013a) Structure of dual receptor binding to botulinum neurotoxin B. Nat Commun 4:2058. doi:10.1038/ncomms3058

  • Berntsson RP, Peng L, Svensson LM, Dong M, Stenmark P (2013b) Crystal structures of botulinum neurotoxin DC in complex with its protein receptors synaptotagmin I and II. Structure. 21(9):1602–1611. doi:10.1016/j.str.2013.1606.1026. Epub 2013 Aug 1608

  • Blum FC, Chen C, Kroken AR, Barbieri JT (2012) Tetanus toxin and botulinum toxin a utilize unique mechanisms to enter neurons of the central nervous system. Infect Immun 80(5):1662–1669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blum FC, Przedpelski A, Tepp WH, Johnson EA, Barbieri JT (2014a) Entry of a recombinant, full-length, atoxic tetanus neurotoxin into Neuro-2a cells. Infect Immun 82(2):873–881

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Blum FC, Tepp WH, Johnson EA, Barbieri JT (2014b) Multiple domains of tetanus toxin direct entry into primary neurons. Traffic 15(10):12197

    Article  CAS  Google Scholar 

  • Bohnert S, Schiavo G (2005) Tetanus toxin is transported in a novel neuronal compartment characterized by a specialized pH regulation. J Biol Chem 280(51):42336–42344

    Article  CAS  PubMed  Google Scholar 

  • Bohnert S, Deinhardt K, Salinas S, Schiavo G (2006) Uptake and transport of clostridium neurotoxins. Alouf JE, Popoff MR (eds) The sourcebook of comprehensive bacterial protein toxins. Amsterdam, Elsevier Academic Press pp 390–408

    Google Scholar 

  • Bonventre PF (1979) Absorption of botulinal toxin from the gastrointestinal tract. Rev Infect Dis 1(4):663–667

    Article  CAS  PubMed  Google Scholar 

  • Breidenbach MA, Brunger AT (2005) 2.3 A crystal structure of tetanus neurotoxin light chain. Biochemistry 44(20):7450–7457

    Article  CAS  PubMed  Google Scholar 

  • Brüggemann H, Bäumer S, Fricke WF, Wiezr A, Liesagang H, Decker I, Herzberg C, Martinez-Arias R, Henne A, Gottschalk G (2003) The genome sequence of Clostridium tetani, the causative agent of tetanus disease. Proc. Ntl. Acad. Sci. (USA) 100:1316–1321

    Article  CAS  Google Scholar 

  • Bryant AM, Davis J, Cai S, Singh BR (2013) Molecular composition and extinction coefficient of native botulinum neurotoxin complex produced by Clostridium botulinum hall A strain. Protein J 32(2):106–117. doi:10.1007/s10930-10013-19465-10936

  • Caleo M, Schiavo G (2009) Central effects of tetanus and botulinum neurotoxins. Toxicon 54(5):593–599

    Article  CAS  PubMed  Google Scholar 

  • Caleo M, Antonucci F, Restani L, Mazzocchio R (2009) A reappraisal of the central effects of botulinum neurotoxin type A: by what mechanism? J Neurochem 109(1):15–24

    Article  CAS  PubMed  Google Scholar 

  • Call JE, Cooke PH, Miller AJ (1995) In situ characterization of Clostridium botulinum neurotoxin synthesis and export. J Appl Bacteriol 79:257–263

    Article  CAS  PubMed  Google Scholar 

  • Capaldo CT, Macara IG (2007) Depletion of E-cadherin disrupts establishment but not maintenance of cell junctions in Madin-Darby canine kidney epithelial cells. Mol Biol Cell 18(1):189–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carter AT, Paul CJ, Mason DR, Twine SM, Alston MJ, Logan SM, Austin JW, Peck MW (2009) Independent evolution of neurotoxin and flagellar genetic loci in proteolytic Clostridium botulinum. BMC Genom 10:115

    Article  CAS  Google Scholar 

  • Carter AT, Stringer SC, Webb MD, Peck MW (2013) The type F6 neurotoxin gene cluster locus of group II Clostridium botulinum has evolved by successive disruption of two different ancestral precursors. Genome Biol Evol 5(5):1032–1037

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chadda R, Howes MT, Plowman SJ, Hancock JF, Parton RG, Mayor S (2007) Cholesterol-sensitive Cdc42 activation regulates actin polymerization for endocytosis via the GEEC pathway. Traffic 8(6):702–717

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Gumbiner BM (2006) Crosstalk between different adhesion molecules. Curr Opin Cell Biol 18(5):572–578

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Korkeala H, Aarnikunnas J, Lindström M (2007) Sequencing the botulinum neurotoxin gene and related genes in Clostridium botulinum type E strains reveals orfx3 and a novel type E neurotoxin subtype. J Bacteriol 189(23):8643–8650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen C, Baldwin MR, Barbieri JT (2008) Molecular basis for tetanus toxin coreceptor interactions. Biochemistry 47(27):7179–7186

    Article  CAS  PubMed  Google Scholar 

  • Chen C, Fu Z, Kim JJ, Barbieri JT, Baldwin MR (2009) Gangliosides as high affinity receptors for tetanus neurotoxin. J Biol Chem 284(39):26569–26577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng LW, Stanker LH, Henderson TD 2nd, Lou J, Marks JD (2009) Antibody protection against botulinum neurotoxin intoxication in mice. Infect Immun 77(10):4305–4313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng ZJ, Singh RD, Holicky EL, Wheatley CL, Marks DL, Pagano RE (2010) Co-regulation of caveolar and Cdc42-dependent fluid phase endocytosis by phosphocaveolin-1. J Biol Chem 285(20):15119–15125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coffield JA, Bakry NM, Maksymowych AB, Simpson LL (1999) Characterization of a vertebrate neuromuscular junction that demonstrates selective resistance to botulinum toxin. J Pharmacol Exp Ther 289(3):1509–1516

    CAS  PubMed  Google Scholar 

  • Connan C, Varela-Chavez C, Mazuet C, Molgo J, Haustant GM, Disson O, Lecuit M, Vandewalle A, Popoff MR (2016) Translocation and dissemination to target neurons of botulinum neurotoxin type B in the mouse intestinal wall. Cell Microbiol 18(2):282–301

    Article  CAS  PubMed  Google Scholar 

  • Connan C, Voillequin, M, Varela Chavez, C, Mazuet, C, Leveque, C, Vitry, S, Vandewalle, A, Popoff, MR (2017) Botulinum neurotoxin type B uses a distinct entry pathway mediated by Cdc42 into intestinal cells versus neuronal cells. Cell Microbiol 19 (8). doi:10.1111/cmi.12738

  • Couesnon A, Pereira Y, Popoff MR (2008) Receptor-mediated transcytosis of botulinum neurotoxin A through intestinal cell monolayers. Cell Microbiol 10(2):375–387

    CAS  PubMed  Google Scholar 

  • Couesnon A, Shimizu T, Popoff MR (2009) Differential entry of botulinum neurotoxin A into neuronal and intestinal cells. Cell Microbiol 11(2):289–308

    Article  CAS  PubMed  Google Scholar 

  • Couesnon A, Colasante C, Molgo J, Popoff MR (2010) Differential entry of Botulinum neurotoxin A into neuronal and intestinal cells: an ultrastructural approach. Botulinum J. 1(4):375–392

    Article  Google Scholar 

  • Couesnon A, Molgo J, Connan C, Popoff MR (2012) Preferential entry of botulinum neurotoxin A Hc domain trhough intestinal crypt cells and targeting to cholinergic neurons of the mouse intestine. PLoS Pathog 8(3):e1002583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deinhardt K, Berminghausen O, Willison HJ, Hopkins CR, Schiavo G (2006a) Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1. J Cell Biol 174:459–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deinhardt K, Salinas S, Verastegui C, Watson R, Worth D, Hanrahan S, Bucci C, Schiavo G (2006b) Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52(2):293–305

    Article  CAS  PubMed  Google Scholar 

  • Dineen SS, Bradshaw M, Johnson EA (2003) Neurotoxin gene clusters in Clostridium botulinum type A strains: sequence comparison and evolutionary implications. Cur. Microbiol. 46(5):342–352

    Article  CAS  Google Scholar 

  • Dong M, Richards DA, Goodnough MC, Tepp WH, Johnson EA, Chapman ER (2003) Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells. J Cell Biol 162:1293–1303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dong M, Yeh F, Tepp WH, Dean C, Johnson EA, Janz R, Chapman ER (2006) SV2 Is the Protein Receptor for Botulinum Neurotoxin A. Science 312:592–596

    Article  CAS  PubMed  Google Scholar 

  • Dong M, Liu H, Tepp WH, Johnson EA, Janz R, Chapman ER (2008) Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Mol Biol Cell 19(12):5226–5237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dover N, Barash JR, Burke JN, Hill KK, Detter JC, Arnon SS (2014) Arrangement of the Clostridium baratii F7 toxin gene cluster with identification of a sigma factor that recognizes the botulinum toxin gene cluster promoters. PLoS One 9(5): e97983. doi:10.1371/journal.pone.0097983.eCollection.0092014

  • Eisele KH, Fink K, Vey M, Taylor HV (2011) Studies on the dissociation of botulinum neurotoxin type A complexes. Toxicon 57(4):555–565

    Article  CAS  PubMed  Google Scholar 

  • Eleopra R, Tugnoli V, Rossetto O, De Grandis D, Montecucco C (1998) Different time courses of recovery after poisoning with botulinum neurotoxin serotypes A and E in humans. Neurosci Lett 256:135–138

    Article  CAS  PubMed  Google Scholar 

  • Elias M, Al-Saleem F, Ancharski DM, Singh A, Nasser Z, Olson RM, Simpson LL (2011) Evidence that botulinum toxin receptors on epithelial cells and neuronal cells are not identical: implications for development of a non-neurotropic vaccine. J Pharmacol Exp Ther 336(3):605–612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emsley P, Fotinou C, Black I, Fairweather NF, Charles IG, Watts C, Hewitt E, Isaacks NW (2000) The structures of the Hc fragment of Tetanus Toxin with carbohydrate subunit complexes provide insight into ganglioside binding. J Biol Chem 275(12):8889–8894

    Article  CAS  PubMed  Google Scholar 

  • Eswaramoorthy S, Sun J, Li H, Singh BR, Swaminathan S (2015) Molecular Assembly of Clostridium botulinum progenitor M complex of type E. Sci Rep 5:17795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evergren E, Gad H, Walther K, Sundborger A, Tomilin N, Shupliakov O (2007) Intersectin is a negative regulator of dynamin recruitment to the synaptic endocytic zone in the central synapse. J Neurosci 27(2):379–390

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Alfonso T, Kwan R, Ryan TA (2006) Synaptic vesicles interchange their membrane proteins with a large surface reservoir during recycling. Neuron 51(2):179–186

    Article  CAS  PubMed  Google Scholar 

  • Fischer A, Montal M (2013) Molecular dissection of botulinum neurotoxin reveals interdomain chaperone function. Toxicon 75:101–107

    Article  CAS  PubMed  Google Scholar 

  • Fisher A (2013) Synchronized chaperone function of botulinum neurotoxin domains mediates light chain translocation into neurons. In: Rummel BT Berlin A (eds) Cur topics microbiol immunol, vol 364. Springer-Verlag, pp 115–137

    Google Scholar 

  • Foran PG, Mohammed N, Lisk GO, Nagwaney S, Lawrence GW, Johnson E, Smith L, Aoki KR, Dolly OJ (2003) Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E and F compared with the long lasting type A. J Biol Chem 278:1363–1371

    Article  CAS  PubMed  Google Scholar 

  • Fotinou C, Emsley P, Black I, Ando H, Ishida H, Kiso M, Sinha KA, Fairweather NF, Isaacs NW (2001) The crystal structure of Tetanus Toxin Hc fragment complexed with a synthetic GT1b analogue suggests cross-linking between ganglioside receptors and the toxin. J Biol Chem 276(34):3274–3281

    Article  Google Scholar 

  • Fu Z, Chen S, Baldwin MR, Boldt GE, Crawford A, Janda KD, Barbieri JT, Kim JJ (2006) Light chain of botulinum neurotoxin serotype A: structural resolution of a catalytic intermediate. Biochemistry 45(29):8903–8911

    Article  CAS  PubMed  Google Scholar 

  • Fu Z, Chen C, Barbieri JT, Kim JJ, Baldwin MR (2009) Glycosylated SV2 and gangliosides as dual receptors for botulinum neurotoxin serotype F. Biochemistry 48(24):5631–5641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujinaga Y, Inoue K, Shimazaki S, Tomochika K, Tsuzuki K, Fujii N, Watanabe T, Ohyama T, Takeshi K, Inoue K, Oguma K (1994) Molecular construction of Clostridium botulinum type C progenitor toxin and its gene organization. Biochem Biophys Res Commun 205:1291–1298

    Article  CAS  PubMed  Google Scholar 

  • Fujinaga Y, Inoue K, Watanabe S, Yokota K, Hirai Y, Nagamachi E, Oguma K (1997) The haemagglutinin of Clostridium botulinum type C progenitor toxin plays an essential role in binding of toxin to the epithelial cells of guinea pig intestine, leading to the efficient absorption of the toxin. Microbiol. 143(12):3841–3847

    Article  CAS  Google Scholar 

  • Fujinaga Y, Inoue K, Nomura T, Sasaki J, Marvaud JC, Popoff MR, Kozaki S, Oguma K (2000) Identification and characterization of functional subunits of Clostridium botulinum type A progenitor toxin involved in binding to intestinal microvilli and erythrocytes. FEBS Lett 467(2–3):179–183

    Article  CAS  PubMed  Google Scholar 

  • Fujinaga Y, Wolf AA, Rodighiero C, Wheeler HE, Tsai B, Allen L, Jobling MG, Rapoport T, Holmes RK, Lencer WI (2003) Gangliosides that associate with lipid rafts mediate transport of cholera and related toxins from the plasma membrane to endoplasmic reticulum. Mol Biol Cell 14:4783–4793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujinaga Y, Inoue K, Watarai S, Sakaguchi G, Arimitsu H, Lee JC, Jin Y, Matsumura T, Kabumoto Y, Watanabe T, Ohyama T, Nishikawa A, Oguma K (2004) Molecular characterization of binding subcomponents of Clostridium botulinum type C progenitor toxin for intestinal epithelial cells and erythrocytes. Microbiol. 150(5):1529–1538

    Article  CAS  Google Scholar 

  • Fujinaga Y, Matsumura T, Jin Y, Takegahara Y, Sugawara Y (2009) A novel function of botulinum toxin-associated proteins: HA proteins disrupt intestinal epithelial barrier to increase toxin absorption. Toxicon 54(5):583–586

    Article  CAS  PubMed  Google Scholar 

  • Fujinaga Y, Sugawara Y, Matsumura T (2013) Uptake of botulinum neurotoxin in the intestine. Curr Top Microbiol Immunol 364:45–59

    CAS  PubMed  Google Scholar 

  • Galloux M, Vitrac H, Montagner C, Raffestin S, Popoff MR, Chenal A, Forge V, Gillet D (2008) Membrane Interaction of botulinum neurotoxin A translocation (T) domain. The belt region is a regulatory loop for membrane interaction. J Biol Chem 283(41):27668–27676

    Article  CAS  PubMed  Google Scholar 

  • Gauthier NC, Monzo P, Kaddai V, Doye A, Ricci V, Boquet P (2005) Helicobacter pylro VacA cytotoxin: a probe for a clathrin-independent and Cdc42-dependent pinocytic pathway routed to late endosomes. Mol Biol Cell 16(10):4852–4866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giordani F, Fillo S, Anselmo A, Palozzi AM, Fortunato A, Gentile B, Azarnia Tehran D, Ciammaruconi A, Spagnolo F, Pittiglio V, Anniballi F, Auricchio B, De Medici D, Lista F (2015) Genomic characterization of Italian Clostridium botulinum group I strains. Infect Genet Evol 36:62–71

    Google Scholar 

  • Granseth B, Odermatt B, Royle SJ, Lagnado L (2006) Clathrin-mediated endocytosis is the dominant mechanism of vesicle retrieval at hippocampal synapses. Neuron 51(6):773–786

    Article  CAS  PubMed  Google Scholar 

  • Gu S, Jin R (2013) Assembly and function of the botulinum neurotoxin progenitor complex. Curr Top Microbiol Immunol 364:21–44. doi:10.1007/978-3-642-33570-9_2

  • Gu S, Rumpel S, Zhou J, Strotmeier J, Bigalke H, Perry K, Shoemaker CB, Rummel A, Jin R (2012) Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science 335(6071):977–981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gumbiner BM (1996) Cell adhesion; the molecular basis of tissue architecture and morphogenesis. Cell 84:345–357

    Article  CAS  PubMed  Google Scholar 

  • Harper CB, Martin S, Nguyen TH, Daniels SJ, Lavidis NA, Popoff MR, Hadzic G, Mariana A, Chau N, McCluskey A, Robinson PJ, Meunier FA (2011) Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism. J Biol Chem 286:35966–35976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hartsock A, Nelson WJ (2008) Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 1778:660–669

    Article  CAS  PubMed  Google Scholar 

  • Hasegawa K, Watanabe T, Suzuki T, Yamano A, Oikawa T, Sato Y, Kouguchi H, Yoneyama T, Niwa K, Ikeda T, Ohyama T (2007) A novel subunit structure of Clostridium botulinum serotype D toxin complex with three extended arms. J Biol Chem 282(34):24777–24783

    Article  CAS  PubMed  Google Scholar 

  • Herreros J, Ng T, Schiavo G (2001) Lipid rafts act as specialized domains for tetanus toxin binding and internalization into neurons. Mol Biol Cell 12:2947–2960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hill KK, Smith TJ (2013) Genetic diversity within Clostridium botulinum serotypes, botulinum neurotoxin gene clusters and toxin subtypes. Curr Top Microbiol Immunol 364(doi):1–20

    Google Scholar 

  • Hill KK, Smith TJ, Helma CH, Ticknor LO, Foley BT, Svensson RT, Brown JL, Johnson EA, Smith LA, Okinaka RT, Jackson PJ, Marks JD (2007) Genetic diversity among botulinum neurotoxin-producing clostridial strains. J Bacteriol 189(3):818–832

    Article  CAS  PubMed  Google Scholar 

  • Hill KK, Xie G, Foley BT, Smith TJ (2015) Genetic diversity within the botulinum neurotoxin-producing bacteria and their neurotoxins. Toxicon 107:2–8ki

    Google Scholar 

  • Hines HB, Lebeda F, Hale M, Brueggemann EE (2005) Characterization of botulinum progenitor toxins by mass spectrometry. Appl Environ Microbiol 71(8):4478–4486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hughes JM, Blumenthal JR, Merson MH, Lombard GL, Dowell VR Jr, Gangarosa EJ (1981) Clinical features of types A and B food-borne botulism. Ann Intern Med 95(4):442–445

    Article  CAS  PubMed  Google Scholar 

  • Inoue K, Fujinaga Y, Watanabe T, Ohyama T, Takeshi K, Moriishi K, Nakajima H, Inoue K, Oguma K (1996) Molecular composition of Clostridium botulinum type A progenitor toxins. Infect Immun 64(5):1589–1594

    CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue K, Fujinaga Y, Honke K, Yokota K, Ikeda T, Ohyama T, Takeshi K, Watanabe T, Inoue K, Oguma K (1999) Characterization of haemagglutinin activity of Clostridium botulinum type C and D 16S toxins, and one subcomponent of haemagglutinin (HA1). Microbiol 145:2533–2542

    Article  CAS  Google Scholar 

  • Inoue K, Fujnaga Y, Honke K, Arimitsu H, Mahmut N, Sakaguchi G, Ohyama T, Watanabe T, Inoue K, Oguma K (2001) Clostridium botulinum type A haemagglutinin positive progenitor toxin (HA+-PTX) binds to oligosaccharides containing Galb1-4GlcNAc through one subcomponent of haemagglutinin (HA1). Microbiol. 147:811–819

    Article  CAS  Google Scholar 

  • Inoue K, Sobhany M, Transue TR, Oguma K, Pedersen LC, Negishi M (2003) Structural analysis by X-ray crystallography and calorimetry of a haemagglutinin component (HA1) of the progenitor toxin from Clostridium botulinum. Microbiology 149:3361–3370

    Article  CAS  PubMed  Google Scholar 

  • Inui K, Ito H, Miyata K, Matsuo T, Horiuchi R, Ikeda T, Watanabe T, Ohyama T, Niwa K (2010) Involvement of sialic acid in transport of serotype C1 botulinum toxins through rat intestinal epithelial cells. J Vet Med Sci 72(9):1251–1255

    Article  CAS  PubMed  Google Scholar 

  • Inui K, Sagane Y, Miyata K, Miyashita S, Suzuki T, Shikamori Y, Ohyama T, Niwa K, Watanabe T (2012) Toxic and nontoxic components of botulinum neurotoxin complex are evolved from a common ancestral zinc protein. Biochem Biophys Res Commun 419(3):500–504

    Article  CAS  PubMed  Google Scholar 

  • Ito H, Sagane Y, Miyata K, Inui K, Matsuo T, Horiuchi R, Ikeda T, Suzuki T, Hasegawa K, Kouguchi H, Oguma K, Niwa K, Ohyama T, Watanabe T (2011) HA-33 facilitates transport of the serotype D botulinum toxin across a rat intestinal epithelial cell monolayer. FEMS Immunol Med Microbiol 61(3):323–331

    Article  CAS  PubMed  Google Scholar 

  • Jenzer G, Mumenthaler M, Ludin HP, Robert F (1975) Autonomic dysfunction in botulism B: a clinical report. Neurology 25(2):150–153

    Article  CAS  PubMed  Google Scholar 

  • Jepson MA, Clark MA (1998) Studying M cells and their role in infection. Trends Microbiol 6(9):359–365

    Article  CAS  PubMed  Google Scholar 

  • Jin Y, Takegahara Y, Sugawara Y, Matsumura T, Fujinaga Y (2009) Disruption of the epithelial barrier by botulinum haemagglutinin (HA) proteins—Differences in cell tropism and the mechanism of action between HA proteins of types A or B, and HA proteins of type C. Microbiology 155(Pt 1):35–45

    Article  CAS  PubMed  Google Scholar 

  • Karalewitz AP, Fu Z, Baldwin MR, Kim JJ, Barbieri JT (2012) Botulinum neurotoxin serotype C associates with dual ganglioside receptors to facilitate cell entry. J Biol Chem 287(48):40806–40816. doi:10.1074/jbc.M40112.404244. Epub 402012 Oct 404241

  • Keller JE (2006) Recovery from botulinum neurotoxin poisoning in vivo. Neuroscience 139(2):629–637 Epub 2006 Feb 2020

    Article  CAS  PubMed  Google Scholar 

  • Keller JE, Neale EA, Oyler G, Adler M (1999) Persistence of botulinum neurotoxin action in cultured spinal cord cells. FEBS Lett 456:137–142

    Article  CAS  PubMed  Google Scholar 

  • Keller JE, Cai F, Neale EA (2004) Uptake of botulinum neurotoxin into cultured neurons. Biochem. 43(2):526–532

    Article  CAS  Google Scholar 

  • Kerneis S, Bogdanova A, Kraenhenbul JP, Pringault E (1997) Conversion by Payer’s patche lymphocyte of human enterocytes into M cells that transport bacteria. Science 277:949–952

    Article  CAS  PubMed  Google Scholar 

  • Kerneis S, Caliot E, Stubbe H, Bogdanova A, Kraehenbuhl J, Pringault E (2000) Molecular studies of the intestinal mucosal barrier physiopathology using cocultures of epithelial and immune cells: a technical update. Microbes Infect 2(9):1119–1124

    Article  CAS  PubMed  Google Scholar 

  • Kitamura M, Sakaguchi S, Sakaguchi G (1969) Significance of 12S toxin of Clostridium botulinum type E. J Bacteriol 98(3):1173–1178

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kitamura M, Takamiya K, Aizawa S, Furukawa K (1999) Gangliosides are the binding substances in neural cells for tetanus and botulinum toxins in mice. Biochim Biophys Acta 1441:1–3

    Article  CAS  PubMed  Google Scholar 

  • Kitamura M, Igimi S, Furukawa K, Furukawa K (2005) Different response of the knockout mice lacking b-series gangliosides against botulinum and tetanus toxins. Biochim Biophys Acta 1741:1–3

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi H, Fujisawa K, Saito Y, Kamijo M, Oshima S, Kubo M, Eto Y, Monma C, Kitamura M (2003) A botulism case of a 12-year-old girl caused by intestinal colonization of Clostridium botulinum type Ab. Jpn J Infect Dis 56(2):73–74

    PubMed  Google Scholar 

  • Koizumi H, Goto S, Okita S, Morigaki R, Akaike N, Torii Y, Harakawa T, Ginnaga A, Kaji R (2014) Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2. Front Neurol 5:98

    Article  PubMed  PubMed Central  Google Scholar 

  • Kojima S, Eguchi H, Ookawara T, Fujiwara N, Yasuda J, Nakagawa K, Yamamura T, Suzuki K (2005) Clostridium botulinum type A progenitor toxin binds to Intestine-407 cells via N-acetyllactosamine moiety. Biochem Biophys Res Commun 331(2):571–576

    Article  CAS  PubMed  Google Scholar 

  • Kouguchi H, Watanabe T, Sagane Y, Sunagawa H, Ohyama T (2002) In vitro reconstitution of the Clostridium botulinum type D progenitor toxin. J Biol Chem 277(4):2650–2656

    Article  CAS  PubMed  Google Scholar 

  • Kozaki S, Kamata Y, Nishiki T, Kakinuma H, Maruyama H, Takahashi H, Karasawa T, Yamakawa K, Nakamura S (1998) Characterization of Clostridium botulinum type B neurotoxin associated with infant botulism in Japan. Infect Immun 66(10):4811–4816

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kumaran D, Eswaramoorthy S, Furey W, Navaza J, Sax M, Swaminathan S (2009) Domain organization in Clostridium botulinum neurotoxin type E is unique: its implication in faster translocation. J Mol Biol 386(1):233–245

    Article  CAS  PubMed  Google Scholar 

  • Lacy DB, Stevens RC (1999) Sequence homology and structural analysis of the clostridial neurotoxins. J Mol Biol 291(5):1091–1104

    Article  CAS  PubMed  Google Scholar 

  • Lacy DB, Tepp W, Cohen AC, Das Gupta BR, Stevens RC (1998) Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nature Struct. Biol 5(10):898–902

    Google Scholar 

  • Lalli G, Schiavo G (2002) Analysis of retrograde transport in motor neurons reveals common endocytic carriers for tetanus toxin and neutrophin receptor p75NTR. J Cell Biol 156:233–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lalli G, Bohnert S, Deinhardt K, Verastegui C, Schiavo G (2003) The journey of tetanus and botulinum neurotoxins in neurons. Trends Microbiol 11:431–437

    Article  CAS  PubMed  Google Scholar 

  • Lam KH, Yao, G Jin R (2015a) Diverse binding modes, same goal: the receptor recognition mechanism of botulinum neurotoxin. Prog Biophys Mol Biol

    Google Scholar 

  • Lam TI, Stanker LH, Lee K, Jin R, Cheng LW (2015b) Translocation of botulinum neurotoxin serotype A and associated proteins across the intestinal epithelia. Cell Microbiol 17(8):1133–1143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamaze C, Johannes L. (2006a) Intracellular trafficking of bacterial and plant protein toxins. In: Alouf JE, Popoff MR (eds) The sourcebook of bacterial protein toxins. Amsterdam, Elsevier Academic Press, pp 35–153

    Google Scholar 

  • Lamaze C, Johannes L (2006b) Intracellular trafficking of bacterial and plant toxins. In: Alouf JE, Popoff MR (eds) The comprehensive sourcebook of bacterial protein toxins. Amsterdam, Elsevier-Academic Press, pp 135–153

    Google Scholar 

  • Lee K, Gu S, Jin L, Le TT, Cheng LW, Strotmeier J, Kruel AM, Yao G, Perry K, Rummel A, Jin R (2013) Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathog 9(10): e1003690. doi:10.1371/journal.ppat.1003690. Epub 1002013 Oct 1003610

  • Lee K, Zhong X, Gu S, Kruel AM, Dorner MB, Perry K, Rummel A, Dong M, Jin R (2014) Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex. Science 344(6190):1405–1410. doi:10.1126/science.1253823

  • Li B, Qian X, Sarkar HK, Singh BR (1998) Molecular characterization of type E Clostridium botulinum and comparison to other types of Clostridium botulinum. Biochim Biophys Acta 1395:21–27

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Foran P, Lawrence G, Mohammed N, Chan-Kwo-Chion C, Lisk G, Aoki R, Dolly O (2001) Recombinant forms of tetanus toxin engineered for examining and exploiting neuronal trafficking pathways. J Biol Chem 276:31394–31401

    Article  CAS  PubMed  Google Scholar 

  • Lietzow MA, Gielow ET, Le D, Zhang J, Verhagen MF (2008) Subunit stoichiometry of the Clostridium botulinum type A neurotoxin complex determined using denaturing capillary electrophoresis. Protein J 27(7–8):420–425

    Article  CAS  PubMed  Google Scholar 

  • Lin G, Tepp WH, Pier CL, Jacobson MJ, Johnson EA (2010) Expression of the Clostridium botulinum A2 neurotoxin gene cluster proteins and characterization of the A2 complex. Appl Environ Microbiol 76(1):40–47

    Article  CAS  PubMed  Google Scholar 

  • Macdonald TE, Helma CH, Shou Y, Valdez YE, Ticknor LO, Foley BT, Davis SW, Hannett GE, Kelly-Cirino CD, Barash JR, Arnon SS, Lindstrôm M, Korkeala H, Smith LA, Smith TJ, Hill KK (2011) Analysis of Clostridium botulinum serotype E strains by using multilocus sequence typing, amplified fragment length polymorphism, variable-number tandem-repeat analysis, and botulinum neurotoxin gene sequencing. Appl Environ Microbiol 77(24):8625–8634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahmut N, Inoue K, Fujinaga Y, Hughes L, Arimitsu H, Sakaguchi G, Ohtsuka A, Murakami T, Yokota K, Oguma K (2002) Characterization of monoclonal antibodies against haemagglutinin associated with Clostridium botulinum type C neurotoxin. J Med Microbiol 51:286–294

    Article  CAS  PubMed  Google Scholar 

  • Mahrhold S, Rummel A, Bigalke H, Davletov B, Binz T (2006) The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett 580:2011–2014

    Article  CAS  PubMed  Google Scholar 

  • Maksymowych AB, Simpson LL (1998) Binding and transcytosis of botulinum neurotoxin by polarized human carcinoma cells. J Biol Chem 273(34):21950–21957

    Article  CAS  PubMed  Google Scholar 

  • Maksymowych AB, Simpson LI (2004) Structural features of the botulinum neurotoxin molecule that govern binding and transcytosis across polarized human intestinal epithelial cells. J Pharmacol Exp Ther 310(2):633–641

    Article  CAS  PubMed  Google Scholar 

  • Maskos U, Kissa K, St Cloment C, Brulet P (2002) Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice. Proc Natl Acad Sci USA 99(15):10120–10125

    Google Scholar 

  • Maslanka SE, Luquez C, Dykes JK, Tepp WH, Pier CL, Pellett S, Raphael BH, Kalb SR, Barr JR, Rao A, Johnson EA (2016) A novel botulinum neurotoxin, previously reported as serotype H, has a hybrid-like structure with regions of similarity to the structures of serotypes A and F and is neutralized with serotype A antitoxin. J Infect Dis 213(3):379–385

    Article  PubMed  Google Scholar 

  • Matak I, Riederer P, Lackovic Z (2012) Botulinum toxin’s axonal transport from periphery to the spinal cord. Neurochem Int 61(2):236–239

    Article  CAS  PubMed  Google Scholar 

  • Matsumura T, Jin Y, Kabumoto Y, Takegahara Y, Oguma K, Lencer WI, Fujinaga Y (2008) The HA proteins of botulinum toxin disrupt intestinal epithelial intercellular junctions to increase toxin absorption. Cell Microbiol 10(2):355–364

    CAS  PubMed  Google Scholar 

  • Matsumura T, Sugawara Y, Yutani M, Amatsu S, Yagita H, Kohda T, Fukuoka S, Nakamura Y, Fukuda S, Hase K, Ohno H, Fujinaga Y (2015) Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity. Nat Commun 6:6255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayor S, Pagano RE (2007) Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol 8(8):603–612

    Article  CAS  PubMed  Google Scholar 

  • Mayor S, Rao M (2004) Rafts: scale-dependent, active lipid organization at the cell surface. Traffic 5:221–240

    Article  CAS  Google Scholar 

  • Mazuet C, Sautereau J, Legeay C, Bouchier C, Bouvet P, Popoff MR (2015) An atypical outbreak of food-borne botulism due to Clostridium botulinum types B and E from ham. J Clin Microbiol 53(2):722–726. doi:10.1128/JCM.02942-02914. Epub 02014 Nov 02926

  • McClane BA (2006) Clostridium perfringens enterotoxin. In: Alouf JE, Popoff MR (eds) The comprehensive sourcebook of bacterial protein toxins. Amsterdam, Elsevier, Academic Press, pp 763–778

    Google Scholar 

  • Meng J, Wang J, Lawrence GW, Dolly JO (2013) Molecular components required for resting and stimulated endocytosis of botulinum neurotoxins by glutamatergic and peptidergic neurons. FASEB J. 27(8):3167–3180. doi:10.1096/fj.3113-228973. Epub 222013 May 228972

  • Merz B, Bigalke H, Stoll G, Naumann M (2003) Botulism type B presenting as pure autonomic dysfunction. Clin Auton Res 13(5):337–338

    Article  CAS  PubMed  Google Scholar 

  • Meunier FA, Lisk G, Sesardic D, Dolly JO (2003) Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins: the extent and duration are dictated by the sites of SNAP-25 truncation. Mol Cell Neurosci 22(4):454–466

    Article  CAS  PubMed  Google Scholar 

  • Montal M (2009) Translocation of botulinum neurotoxin light chain protease by the heavy chain protein-conducting channel. Toxicon 54(5):565–569

    Article  CAS  PubMed  Google Scholar 

  • Montal M (2010) Botulinum neurotoxin: a marvel of protein design. Annu Rev Biochem 79:591–617

    Article  CAS  PubMed  Google Scholar 

  • Mostov KE, Verges M, Altschuler Y (2000) Membrane traffic in polarized epithelial cells. Curr Opin Cell Biol 12:483–490

    Article  CAS  PubMed  Google Scholar 

  • Munro P, Kojima H, Dupont JL, Bossu JL, Poulain B, Boquet P (2001) High sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein. Biochem. Biophys. Res. Comm. 289:623–629

    Article  CAS  PubMed  Google Scholar 

  • Mutoh S, Kouguchi H, Sagane Y, Suzuki T, Hasegawa K, Watanabe T, Ohyama T (2003) Complete subunit structure of the Clostridium botulinum type D complex via intermediate assembly with nontoxic components. Biochem. 42(37):10991–10997

    Article  CAS  Google Scholar 

  • Mutoh S, Suzuki T, Hasegawa K, Nakazawa Y, Kouguchi H, Sagane Y, Niwa K, Watanabe T, Ohyama T (2005) Four molecules of the 33 kDa haemagglutinin component of the Clostridium botulinum serotype C and D toxin complexes are required to aggregate erythrocytes. Microbiology 151(Pt 12):3847–3858

    Article  CAS  PubMed  Google Scholar 

  • Neale EA, Bowers LM, Jia M, Bateman KE, Williamson LC (1999) Botulinum neurotoxin A blocks synaptic vesicle exocytosis but not endocytosis at the nerve terminal. J Cell Biol 147(6):1249–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishikawa A, Uotsu N, Arimitsu H, Lee JC, Miura Y, Fujinaga Y, Nakada H, Watanabe T, Ohyama T, Sakano Y, Oguma K (2004) The receptor and transporter for internalization of Clostridium botulinum type C progenitor toxin into HT-29 cells. Biochem Biophys Res Commun 319(2):327–333

    Article  CAS  PubMed  Google Scholar 

  • Nishiki T, Tokuyama Y, Kamata Y, Nemoto Y, Yoshida A, Sato K, Sekigichi M, Taakahashi M, Kozaki S (1996) The high-affinity of Clostridium botulinum type B neurotoxin to synaptotagmin II associated with gangliosides GT1B/GD1a. FEBS Lett 378:253–257

    Article  CAS  PubMed  Google Scholar 

  • Niwa K, Yoneyama T, Ito H, Taira M, Chikai T, Kouguchi H, Suzuki T, Hasegawa K, Miyata K, Inui K, Ikeda T, Watanabe T, Ohyama T (2010) Sialic acid-dependent binding and transcytosis of serotype D botulinum neurotoxin and toxin complex in rat intestinal epithelial cells. Vet Microbiol 141(3–4):312–320

    Article  CAS  PubMed  Google Scholar 

  • Nuemket N, Tanaka Y, Tsukamoto K, Tsuji T, Nakamura K, Kozaki S, Yao M, Tanaka I (2011) Structural and mutational analyses of the receptor binding domain of botulinum D/C mosaic neurotoxin: Insight into the ganglioside binding mechanism. Biochem Biophys Res Commun

    Google Scholar 

  • Oguma K, Inoue K, Fujinaga Y, Yokota K, Watanabe T, Ohyama T, Takeshi K, Inoue K (1999) Structure and function of Clostridium botulinum progenitor toxin. J. Toxicol. 18:17–34

    CAS  Google Scholar 

  • O’Sullivan GA, Mohammed N, Foran PG, Lawrence GW, Dolly JO (1999) Rescue of exocytosis in botulinum toxin A-poisoned chromaffin cells by expression of cleavage-resistant SNAP-25. J Biol Chem 274:36897–36904

    Article  PubMed  Google Scholar 

  • Ouzilou L, Caliot M, Pelletier I, Prévost MC, Pringault E, Colbère-Garapin F (2002) Poliovirus transcytosis through M-like cells. J Gen Virol 83:2177–2182

    Article  CAS  PubMed  Google Scholar 

  • Park JB, Simpson LL (2003) Inhalation poisoning by botulinum toxin and inhalation vaccination with its heavy-chain component. Infect Immun 71:1147–1154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peck MW, Stringer SC, Carter AT (2011) Clostridium botulinum in the post-genomic era. Food Microbiol 28(2):183–191

    Article  PubMed  Google Scholar 

  • Peck MW, Smith TJ, Anniballi F, Austin JW, Bano L, Bradshaw M, Cuervo P, Cheng LW, Derman Y, Dorner BG, Fisher A, Hill KK, Kalb SR, Korkeala H, Lindstrom M, Lista F, Luquez C, Mazuet C, Pirazzini M, Popoff MR, Rossetto O, Rummel A, Sesardic D, Singh BR, Stringer SC (2017) Historical perspectives and guidelines for botulinum neurotoxin subtype nomenclature. Toxins (Basel) 9:E38.

    Google Scholar 

  • Pellett S, Tepp WH, Scherf JM, Johnson EA (2015) Botulinum neurotoxins can enter cultured neurons independent of synaptic vesicle recycling. PLoS ONE 10(7):e0133737

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Peng L, Tepp WH, Johnson EA, Dong M (2011) Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLoS Pathog 7(3):e1002008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng L, Berntsson RP, Tepp WH, Pitkin RM, Johnson EA, Stenmark P, Dong M (2012) Botulinum neurotoxin D-C uses synaptotagmin I/II as receptors and human synaptotagmin II is not an effective receptor for type B, D-C, and G toxins. J Cell Sci

    Google Scholar 

  • Petro KA, Dyer MA, Yowler BC, Schengrund CL (2006) Disruption of lipid rafts enhances activity of botulinum neurotoxin serotype A. Toxicon 48(8):1035–1045

    Article  CAS  PubMed  Google Scholar 

  • Pier CL, Chen C, Tepp WH, Lin G, Janda KD, Barbieri JT, Pellett S, Johnson EA (2011) Botulinum neurotoxin subtype A2 enters neuronal cells faster than subtype A1. FEBS Lett 585:199–206

    Article  CAS  PubMed  Google Scholar 

  • Pirazzini M, Tehran DA, Leka O, Zanetti G, Rossetto O, Montecucco C (2015a) On the translocation of botulinum and tetanus neurotoxins across the membrane of acidic intracellular compartments. Biochim Biophys Acta

    Google Scholar 

  • Pirazzini M, Tehran DA, Zanetti G, Lista F, Binz T, Shone CC, Rossetto O, Montecucco C (2015b) The thioredoxin reductase—Thioredoxin redox system cleaves the interchain disulphide bond of botulinum neurotoxins on the cytosolic surface of synaptic vesicles. Toxicon 107(Pt A):32–36

    Google Scholar 

  • Polley EH, Vick JA, Ciuchta HP, Fischetti DA, Macchitelli FJ, Montanarelli N (1965) Botulinum toxin, type a: effects on central nervous system. Science 147(3661):1036–1037

    Article  CAS  PubMed  Google Scholar 

  • Popoff MR (1995) Ecology of neurotoxigenic strains of clostridia. Curr Top Microbiol Immunol 195:1–29

    CAS  PubMed  Google Scholar 

  • Popoff MR, Geny B (2009) Multifaceted role of Rho, Rac, Cdc42 and Ras in intercellular junctions, lessons from toxins. Biochim Biophys Acta 1788(4):797–812

    Article  CAS  PubMed  Google Scholar 

  • Popoff MR, Marvaud JC (1999) Structural and genomic features of clostridial neurotoxins. In: Alouf JE, Freer JH (eds) The comprehensive sourcebook of bacterial protein toxins, vol 2. London, Academic Press, pp 174–201

    Google Scholar 

  • Popoff MR, Poulain B (2010) Bacterial toxins and the nervous system: neurotoxins and multipotential toxins interacting with neuronal cells. Toxins (Basel). 2(4):683–737. doi:10.3390/toxins2040683. Epub 2042010 Apr 2040615

  • Potulska-Chromik A, Zakrzewska-Pniewska B, Szmidt-Salkowska E, Lewandowski J, Sinski M, Przyjalkowski W, Kostera-Pruszczyk A (2013) Long lasting dysautonomia due to botulinum toxin B poisoning: clinical-laboratory follow up and difficulties in initial diagnosis. BMC Res Notes. 6:438. doi:10.1186/1756-0500-6-438

  • Poulain B, Popoff MR, Molgo J (2008) How do the botulinum neurotoxins block neurotransmitter release: from botulism to the molecular mechanism of action. Botulinum J. 1(1):14–87

    Article  Google Scholar 

  • Poulain B, Molgo J, Popoff MR (2015) Clostridial neurotoxins: from the cellular and molecular mode of action to their therapeutic use. In: Alouf J., Ladant D, Popoff MR (eds) The comprehensive sourcebook of bacterial protein toxins. Amsterdam, Elsevier pp 287–336

    Google Scholar 

  • Predescu SA, Predescu DN, Timblin BK, Stan RV, Malik AB (2003) Intersectin regulates fission and internalization of caveolae in endothelial cells. Mol Biol Cell 14(12):4997–5010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramachandran R, Heuck AP, Tweten RK, Johnson AE (2002) Structural insights into the membrane-anchoring mechanism of a cholesterol-dependent cytolysin. Nat Struct Biol 9:823–827

    CAS  PubMed  Google Scholar 

  • Raphael BH, Choudoir MJ, Luquez C, Fernandez R, Maslanka SE (2010) Sequence diversity of genes encoding botulinum neurotoxin type F. Appl Environ Microbiol 76(14):4805–4812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Restani L, Antonucci F, Gianfranceschi L, Rossi C, Rossetto O, Caleo M (2011) Evidence for anterograde transport and transcytosis of botulinum neurotoxin A (BoNT/A). J Neurosci 31(44):15650–15659

    Article  CAS  PubMed  Google Scholar 

  • Restani L, Giribaldi F, Manich M, Bercsenyi K, Menendez G, Rossetto O, Caleo M, Schiavo G (2012a) Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog 8(12):e1003087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Restani L, Novelli E, Bottari D, Leone P, Barone I, Galli-Resta L, Strettoi E, Caleo M (2012b) Botulinum neurotoxin a impairs neurotransmission following retrograde transynaptic transport. Traffic 13(8):1083–1089

    Article  CAS  PubMed  Google Scholar 

  • Robertson SL, McClane BA (2011) Interactions between Clostridium perfringens enterotoxin and claudins. Methods Mol Biol 762:63–75

    Article  CAS  PubMed  Google Scholar 

  • Rojas R, Ruiz WG, Leung SM, Jou TS, Apodaca G (2001) Cdc42-dependent modulation of tight junctions and membrane protein traffic in polarized Madin-Darby canine kidney cells. Mol Biol Cell 12:2257–2274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossetto O, Scorzeto M, Megighian A, Montecucco C (2013) Tetanus neurotoxin. Toxicon 66:59–63. doi:10.1016/j.toxicon.2012.1012.1027. Epub 2013 Feb 1016

  • Roux A, Uyhazi K, Frost A, De Camilli P (2006a) GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission. Nature 441(7092):528–531

    Article  CAS  PubMed  Google Scholar 

  • Roux S, Saint Cloment C, Curie T, Girard E, Mena FJ, Barbier J, Osta R, Molgo J, Brulet P (2006b) Brain-derived neurotrophic factor facilitates in vivo internalization of tetanus neurotoxin C-terminal fragment fusion proteins in mature mouse motor nerve terminals. Eur J Neurosci 24(6):1546–1554

    Google Scholar 

  • Rummel A (2013) Double receptor anchorage of botulinum neurotoxins accounts for their exquisite neurospecificity. Curr Top Microbiol Immunol 364:61–90. doi:10.1007/1978-1003-1642-33570-33579_33574

  • Rummel A (2015) The long journey of botulinum neurotoxins into the synapse. Toxicon 107(Pt A):9–24

    Google Scholar 

  • Rummel A, Karnath T, Henke T, Bigalke H, Binz T (2004a) Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G. J Biol Chem 279:30865–30870

    Article  CAS  PubMed  Google Scholar 

  • Rummel A, Mahrhold S, Bigalke H, Binz T (2004b) The Hcc-domain of botulinum neurotoxins A and B exhibits a singular ganglioside binding site displaying serotype specific carbohydrate interaction. Mol Microbiol 51(3):631–643

    Article  CAS  PubMed  Google Scholar 

  • Rummel A, Eichner T, Weil T, Karnath T, Gutcaits A, Mahrhold S, Sandhoff K, Proia RL, Acharya KR, Bigalke H, Binz T (2007) Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept. Proc Natl Acad Sci U S A 104(1):359–364

    Article  CAS  PubMed  Google Scholar 

  • Rummel A, Hafner K, Mahrhold S, Darashchonak N, Holt M, Jahn R, Beermann S, Karnath T, Bigalke H, Binz T (2009) Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. J Neurochem 110(6):1942–1954

    Article  CAS  PubMed  Google Scholar 

  • Sabharanjak S, Sharma P, Parton RG, Mayor S (2002) GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway. Develop. Cell 2(4):411–423

    Article  CAS  Google Scholar 

  • Sagane Y, Watanabe T, Kouguchi H, Sunagawa H, Inoue K, Fujinaga Y, Oguma K, Ohyama T (2000) Characterization of nicking of the nontoxic-nonhemagglutinin components of Clostridium botulinum types C and D progenitor toxin. J Protein Chem 19:575–581

    Article  CAS  PubMed  Google Scholar 

  • Sagane Y, Kouguchi H, Watanabe T, Sunagawa H, Inoue K, Fujinaga Y, Oguma K, Ohyama T (2001) Role of C-terminal region, of HA-33 component of botulinum toxin in hemagglutination. Biochem Biophys Res Commun 288:650–657

    Article  CAS  PubMed  Google Scholar 

  • Schiavo G, Ferrari G, Rossetto O, Montecucco C (1991) Tetanus toxin receptor. Specific cross-linking of tetanus toxin to a protein of NGF-differentiated PC 12 cells. FEBS Lett 290(1–2):227–230

    Article  CAS  PubMed  Google Scholar 

  • Schiavo G, Poulain B, Benfenati F, DasGupta BR, Montecucco C (1993) Novel targets and catalytic activities of bacterial toxins. Trends Microbiol. Sci. 1:170–174

    Article  CAS  Google Scholar 

  • Schmieg N, Berscenyi K, Schiavo G (2015) Upatke and transport of clostridial neurotoxins. In: Alouf J, Ladant D, Popoff MR (eds) The comprehensive sourcebook of bacterial protein toxins. Amsterdam, Elsevier, pp 337–360

    Google Scholar 

  • Sears CL (2001) The toxins of Bacteroides fragilis. Toxicon 39:1737–1746

    Article  CAS  PubMed  Google Scholar 

  • Sears CL, Franco AA, Wu S (2006) Bacteroides fragilis toxins. In: Alouf JE, Popoff MR (eds) The sourcebook of bacterial protein toxins. Amsterdam, Elsevier, Academic Press, pp 535–546

    Google Scholar 

  • Sharma SK, Fu FN, Singh BR (1999) Molecular properties of a hemagglutinin purified from type A Clostridium botulinum. J Protein Chem 18:29–38

    Article  PubMed  Google Scholar 

  • Sharma DK, Choundhury A, Signh RD, Wheatley CL, Marks DL, Pagano RE (2003a) Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge with the clathrin pathway in early endosomes and form microdomains for recycling. J Biol Chem 278:7564–7572

    Article  CAS  PubMed  Google Scholar 

  • Sharma SK, Ramzan MA, Singh BR (2003b) Separation of the components of type A botulinum neeurotoxin complex by electrophoresis. Toxicon 41(3):321–331

    Article  CAS  PubMed  Google Scholar 

  • Shin N, Lee S, Ahn N, Kim SA, Ahn SG, YongPark Z, Chang S (2007) Sorting nexin 9 interacts with dynamin 1 and N-WASP and coordinates synaptic vesicle endocytosis. J Biol Chem 282(39):28939–28950

    Article  CAS  PubMed  Google Scholar 

  • Simpson L (2013) The life history of a botulinum toxin molecule. Toxicon 68(doi):40–59

    Google Scholar 

  • Simpson LL, Coffield JA, Bakry N (1994) Inhibition of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins. J Pharmacol Exp Ther 269(1):256–262

    CAS  PubMed  Google Scholar 

  • Simpson F, Hussain NK, Qualman B, Kelly RB, Kay BK, McPherson PS, Schmid SL (1999) SH3-domain-containing proteins function at distinct steps in clathrin-coated vesicle formation. Nature Cell Biol. 1(2):119–124

    Article  CAS  PubMed  Google Scholar 

  • Singh BR, Li B, Read D (1995) Botulinum versus tetanus neurotoxins: why is botulinum neurotoxin but not tetanus neurotoxin a food poison? Toxicon 33(12):1541–1547

    Article  CAS  PubMed  Google Scholar 

  • Singh BR, Wang T, Kukreja R, Cai S (2014) The botulinum neurotoxin complex and the role of ancillary proteins. In Foster KA (eds) Molecular aspects of botulinum neurotoxin. New York, Springer. 4:68–101

    Google Scholar 

  • Smith TJ, Hill KK, Raphael BH (2015) Historical and Current Perspectives on Clostridium botulinum Diversity. Res Microbiol 166(4):290–302

    Article  PubMed  Google Scholar 

  • Sobel J (2005) Botulism. Clin Infect Dis 41(8):1167–1173

    Article  CAS  PubMed  Google Scholar 

  • Stenmark P, Dupuy J, Imamura A, Kiso M, Stevens RC (2008) Crystal structure of botulinum neurotoxin type A in complex with the cell surface co-receptor GT1b-insight into the toxin-neuron interaction. PLoS Pathog 4(8):e1000129

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Strotmeier J, Mahrhold S, Krez N, Janzen C, Lou J, Marks JD, Binz T, Rummel A (2014) Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A. FEBS Lett 588(7):1087–1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugawara Y, Fujinaga Y (2011) The botulinum toxin complex meets E-cadherin on the way to its destination. Cell Adh Migr 5(1):34–36

    Article  PubMed  PubMed Central  Google Scholar 

  • Sugawara Y, Matsumura T, Takegahara Y, Jin Y, Tsukasaki Y, Takeichi M, Fujinaga Y (2010) Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin. J Cell Biol 189(4):691–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugawara Y, Yutani M, Amatsu S, Matsumura T, Fujinaga Y (2014) Functional Dissection of the Clostridium botulinum Type B Hemagglutinin Complex: Identification of the Carbohydrate and E-Cadherin Binding Sites. PLoS ONE 9(10):e111170. doi:10.11371/journal.pone.0111170.eCollection0112014

  • Sugawara Y, Iwamori M, Matsumura T, Yutani M, Amatsu S, Fujinaga Y (2015) Clostridium botulinum type C hemagglutinin affects the morphology and viability of cultured mammalian cells via binding to the ganglioside GM3. FEBS J 282(17):3334–3347

    Article  CAS  PubMed  Google Scholar 

  • Sugii S, Ohishi I, Sakaguchi G (1977) Intestinal absorption of botulinum toxins of different molecular sizes in rats. Infect Immun 17(3):491–496

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki T, Watanabe T, Mutoh S, Hasegawa K, Kouguchi H, Sagane Y, Fujinaga Y, Oguma K, Ohyama T (2005) Characterization of the interaction between subunits of the botulinum toxin complex produced by serotype D through tryptic susceptibility of the isolated components and complex forms. Microbiology 151(Pt 5):1475–1483

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Miyashita S, Hayashi S, Miyata K, Inui K, Kondo Y, Miyazaki S, Ohyama T, Niwa K, Watanabe T, Sagane Y (2014) Identification of the interaction region between hemagglutinin components of the botulinum toxin complex. Int J Biol Macromol 65:284–288

    Article  CAS  PubMed  Google Scholar 

  • Swaminathan S (2011) Molecular structures and functional relationships in clostridial neurotoxins. Febs J

    Google Scholar 

  • Swaminathan S, Eswaramoorthy S (2000) Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nature Struct. Biol. 7(8):693–699

    Article  CAS  PubMed  Google Scholar 

  • Takei K, Yoshida Y, Yamada H (2005) Regulatory mechanisms of dynamin-dependent endocytosis. J Biochem (Tokyo) 137(3):243–247

    Article  CAS  Google Scholar 

  • Tavallaie M, Chenal A, Gillet D, Pereira Y, Manich M, Gibert M, Raffestin S, Popoff MR, Marvaud JC (2004) Interaction between the two subdomains of the C-terminal part of the botulinum neurotoxin A is essential for the generation of protective antibodies. FEBS Lett 572:299–306

    Article  CAS  PubMed  Google Scholar 

  • Torii Y, Akaike N, Harakawa T, Kato K, Sugimoto N, Goto Y, Nakahira S, Kohda T, Kozaki S, Kaji R, Ginnaga A (2011) Type A1 but not type A2 botulinum toxin decreases the grip strength of the contralateral foreleg through axonal transport from the toxin-treated foreleg of rats. J Pharmacol Sci 117(4):275–285

    Article  CAS  PubMed  Google Scholar 

  • Tsukamoto K, Kohda T, Mukamoto M, Takeuchi K, Ihara H, Saito M, Kozaki S (2005) Binding of Clostridium botulinum types C and D neurotoxins to ganglioside and phospholipid. J Biol Chem 280:35164–35171

    Article  CAS  PubMed  Google Scholar 

  • Umland TC, Wingert LM, Swaminathan S, Furey WF, Schmidt JJ, Sax M (1997) The structure of the receptor binding fragment Hc of tetanus neurotoxin. Nature Struct. Biol. 4(10):788–792

    Article  CAS  PubMed  Google Scholar 

  • Verderio C, Grumelli C, Raiteri L, Coco S, Paluzzi S, Caccin P, Rossetto O, Bonanno G, Montecucco C, Matteoli M (2007) Traffic of botulinum toxins A and E in excitatory and inhibitory neurons. Traffic 8(2):142–153

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Zurawski TH, Meng J, Lawrence GW, Aoki KR, Wheeler L, Dolly JO (2012) Novel chimeras of botulinum and tetanus neurotoxins yield insights into their distinct sites of neuroparalysis. FASEB J. 26(12):5035–5048. doi:10.1096/fj.5012-210112. Epub 212012 Aug 210131

  • Wangroongsarb P, Kohda T, Jittaprasartsin C, Suthivarakom K, Kamthalang T, Umeda K, Sawanpanyalert P, Kozaki S, Ikuta K (2014) Molecular characterization of Clostridium botulinum isolates from foodborne outbreaks in Thailand, 2010. PLoS ONE 9(1):e77792. doi:10.1371/journal.pone.0077792.eCollection0072014

  • Williamson CH, Sahl JW, Smith TJ, Xie G, Foley BT, Smith LA, Fernandez RA, Lindström M, Korkeala H, Keim P, Foster J, Hill K (2016) Comparative genomic analyses reveal broad diversity in botulinum-toxin-producing Clostridia. BMC Genom 17(1):180

    Article  CAS  Google Scholar 

  • Yao G, Lee K, Gu S, Lam KH, Jin R (2014) Botulinum neurotoxin A complex recognizes host carbohydrates through its hemagglutinin component. Toxins (Basel). 6(2):624–635. doi:10.3390/toxins6020624

  • Willjes G, Mahrhold S, Strotmeier J, Eichner T, Rummel A, Binz, T (2013) Botulinum neurotoxin G binds synaptotagmin-II in a mode similar to that of serotype B: tyrosine 1186 and lysine 1191 cause its lower affinity. Biochemistry 17

    Google Scholar 

  • Yao G, Zhang S, Mahrhold S, Lam KH, Stern D, Bagramyan K, Perry K, Kalkum M, Rummel A, Dong M, Jin R (2016) N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A. Nat Struct Mol Biol 23(7):656–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeh FL, Dong M, Yao J, Tepp WH, Lin G, Johnson EA, Chapman ER (2011) SV2 mediates entry of tetanus neurotoxin into central neurons. PLoS Pathog 6(11):e1001207

    Article  CAS  Google Scholar 

  • Yelland TS, Naylor CE, Bagoban T, Savva CG, Moss DS, McClane BA, Blasig IE, Popoff M, Basak AK (2014) Structure of a C. perfringens enterotoxin mutant in complex with a modified Claudin-2 extracellular loop 2. J Mol Biol 426(18):3134–3147

    Article  CAS  PubMed  Google Scholar 

  • Yowler BC, Kensinger RD, Schengrund CL (2002) Botulinum neurotoxin A activity is dependent upon the presence of specific gangliosides in neuroblastoma cells expressing synaptotagmin I. J Biol Chem 277:32815–32819

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Masuyer G, Zhang J, Shen Y, Lundin D, Henriksson L, Miyashita SI, Martinez-Carranza M, Dong M, Stenmark P (2017) Identification and characterization of a novel botulinum neurotoxin. Nat Commun 8:14130

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unité Des Bactéries Anaérobies et Toxines, Institut Pasteur, 25 Rue Du Dr Roux, 75724, Paris Cedex 15, France

    Chloé Connan & Michel R. Popoff

Authors
  1. Chloé Connan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michel R. Popoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel R. Popoff .

Editor information

Editors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Ulm, Germany

    Holger Barth

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Connan, C., Popoff, M.R. (2017). Uptake of Clostridial Neurotoxins into Cells and Dissemination. In: Barth, H. (eds) Uptake and Trafficking of Protein Toxins. Current Topics in Microbiology and Immunology, vol 406. Springer, Cham. https://doi.org/10.1007/82_2017_50

Download citation

Publish with us

Policies and ethics

Search

Navigation