Library Subscription: Guest
Begell Digital Portal Begell Digital Library eBooks Journals References & Proceedings Research Collections
Critical Reviews™ in Immunology
IF: 1.352 5-Year IF: 3.347 SJR: 0.657 SNIP: 0.55 CiteScore™: 2.19

ISSN Print: 1040-8401
ISSN Online: 2162-6472

Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.v30.i2.50
pages 167-187

Mode of Action of Botulinum Neurotoxins: Current Vaccination Strategies and Molecular Immune Recognition

K. Roger Aoki
Ailergan, Inc., 2525 DuPont Drive, Irvine, CA 92612, USA
Leonard A. Smith
Integrated Toxicology Division, US Army Medical Research Institute of Infectious Diseases; Fort Detrick, MD 21702-5011, USA
M. Zouhair Atassi
Baylor College of Medicine

ABSTRACT

The action of a botulinum neurotoxin (BoNT) commences by binding at the nerve terminal via its H- (heavy) chain to a cell-surface receptor, which consists of a ganglioside and a cell-surface protein. Binding enables the L-chain, a Zn2+-dependent endopeptidase, to be internalized and act intracellularly, cleaving one or more SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins required for vesicle docking and fusion, which results in reduced neurotransmitter release. Sprouts emerge at motor-nerve terminals that reestablish synaptic contact and lead to restoration of exocytosis. As the terminals recover, sprouts retreat and synaptic function is fully re-established. Neutralizing antibodies (Abs) induced by vaccination can prevent the neuronal changes produced by BoNT. Until recently, vaccines against BoNT have been based on toxins inactivated by treatment with formaldehyde (toxoids) and contain either one (monovalent) or five (pentavalent) toxoids, but formalin-based toxoids have many undesirable side effects. Availability of the gene sequences of BoNT serotypes enabled design of recombinant subunit vaccines that have included the C-terminal domain of the H chain (HC, its subdomains (HC-N and HC-C), the L- (catalytic) chain, and the L-chain expressed with the translocation domain (LCHN). Of these, the HC displays the highest protective ability. Recent vaccines have used whole toxins inactivated by three key mutations at the enzyme active site, which have been found to be very effective in mice against the correlated toxin. Immune responses to BoNTs A and B epitopes are under the host’s MHC (major histocompatibility complex) control. Anti-BoNT/A blocking Abs bind at sites that coincide or overlap with those that bind synaptosomes and to BoNT/B at sites that overlap with synaptotagmin-II and ganglioside-binding sites. Therefore, locations occupied by blocking Abs preclude the respective toxin from binding to its receptor and thus from binding to cell surface. Information on BoNT epitopes for blocking Abs, sites for binding to cell surface receptors, and T-cell epitopes that provide help to B cells making blocking Abs afford a prospect for rational design of stable synthetic vaccines. These constructs should be clinically useful for epitope-selective modulation of Ab responses to restore effective BoNT treatment in immunoresistant patients.


Articles with similar content:

Structure, Activity, and Immune (T and B Cell) Recognition of Botulinum Neurotoxins
Critical Reviews™ in Immunology, Vol.19, 1999, issue 3
Minako Oshima, M. Zouhair Atassi
Genes for Control of Spread of the Tumor and Mycobacterium tuberculosis Infection in the Mouse
Critical Reviews™ in Immunology, Vol.14, 1994, issue 3-4
Igor K. Egorov, Boris V. Nickonenko
Attractin: Cautionary Tales for Therapeutic Intervention in Molecules with Pleiotropic Functionality
Journal of Environmental Pathology, Toxicology and Oncology, Vol.23, 2004, issue 1
Jonathan S. Duke-Cohan, Abdallah Azouz, Jeong H. Kim
On the Initial Trigger of Myasthenia Gravis and Suppression of the Disease by Antibodies Against the MHC Peptide Region Involved in the Presentation of a Pathogenic T-Cell Epitope
Critical Reviews™ in Immunology, Vol.21, 2001, issue 1-3
Philip Deitiker, Minako Oshima, M. Zouhair Atassi
Ly-49 Receptors and Their Functions
Critical Reviews™ in Immunology, Vol.24, 2004, issue 5
Kerry J. Lavender, Brian J. Ma, Kevin P. Kane