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Cellular Microbiology: Pathogen-Host Cell Molecular Interactions

Tetanus Toxin and Botulinum Toxin A Utilize Unique Mechanisms To Enter Neurons of the Central Nervous System

Faith C. Blum, Chen Chen, Abby R. Kroken, Joseph T. Barbieri
J. B. Bliska, Editor
Faith C. Blum
Medical College of Wisconsin, Microbiology and Molecular Genetics, Milwaukee, Wisconsin, USA
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Chen Chen
Medical College of Wisconsin, Microbiology and Molecular Genetics, Milwaukee, Wisconsin, USA
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Abby R. Kroken
Medical College of Wisconsin, Microbiology and Molecular Genetics, Milwaukee, Wisconsin, USA
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Joseph T. Barbieri
Medical College of Wisconsin, Microbiology and Molecular Genetics, Milwaukee, Wisconsin, USA
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J. B. Bliska
Roles: Editor
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DOI: 10.1128/IAI.00057-12
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ABSTRACT

Botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) are the most toxic proteins for humans. While BoNTs cause flaccid paralysis, TeNT causes spastic paralysis. Characterized BoNT serotypes enter neurons upon binding dual receptors, a ganglioside and a neuron-specific protein, either synaptic vesicle protein 2 (SV2) or synaptotagmin, while TeNT enters upon binding gangliosides as dual receptors. Recently, TeNT was reported to enter central nervous system (CNS) neurons upon synaptic vesicle cycling that was mediated by the direct binding to SV2, implying that TeNT and BoNT utilize common mechanisms to enter CNS neurons. This prompted an assessment of TeNT entry into CNS neurons, using the prototypic BoNT serotype A as a reference for SV2-mediated entry into synaptic vesicles, analyzing the heavy-chain receptor binding domain (HCR) of each toxin. Synaptic vesicle cycling stimulated the entry of HCR/A into neurons, while HCR/T entered neurons with similar levels of efficiency in depolarized and nondepolarized neurons. ImageJ analysis identified two populations of cell-associated HCR/T in synaptic vesicle cycling neurons, a major population which segregated from HCR/A and a minor population which colocalized with HCR/A. HCR/T did not inhibit HCR/A entry into neurons in competition experiments and did not bind SV2, the protein receptor for BoNT/A. Intoxication experiments showed that TeNT efficiently cleaved VAMP2 in depolarized neurons and neurons blocked for synaptic vesicle cycling. These experiments demonstrate that TeNT enters neurons by two pathways, one independent of stimulated synaptic vesicle cycling and one by synaptic vesicles independent of SV2, showing that TeNT and BoNT/A enter neurons by unique mechanisms.

FOOTNOTES

    • Received 17 January 2012.
    • Returned for modification 31 January 2012.
    • Accepted 28 February 2012.
    • Accepted manuscript posted online 5 March 2012.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/IAI.00057-12.

  • Copyright © 2012, American Society for Microbiology. All Rights Reserved.
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Tetanus Toxin and Botulinum Toxin A Utilize Unique Mechanisms To Enter Neurons of the Central Nervous System
Faith C. Blum, Chen Chen, Abby R. Kroken, Joseph T. Barbieri
Infection and Immunity Apr 2012, 80 (5) 1662-1669; DOI: 10.1128/IAI.00057-12

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Tetanus Toxin and Botulinum Toxin A Utilize Unique Mechanisms To Enter Neurons of the Central Nervous System
Faith C. Blum, Chen Chen, Abby R. Kroken, Joseph T. Barbieri
Infection and Immunity Apr 2012, 80 (5) 1662-1669; DOI: 10.1128/IAI.00057-12
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