The botulinum neurotoxins (BoNTs) are the most toxic proteins for humans and have been classified as Category A toxins by the Centers for Disease Control and Prevention. In addition to the natural routes of intoxication (food borne botulism, cutaneous botulism, and infant botulism), inhalation botulism has been proposed as a delivery mechanism for malicious activity. Current vaccines and therapies against botulism are in limited supply for the general public. There are seven serotypes of BoNTs (termed A-G) based upon cross sero-protection. As proof of principle, a subunit vaccine was been produced that protected against intoxication by the seven serotypes of BoNT. This application will continue to develop vaccines and therapies against botulism and characterize the BoNT dual-receptors on neurons.
The aims of this application are to optimize subunit BoNT vaccines that neutralize the seven serotypes of BoNT, to characterize a """"""""new"""""""" BoNT serotype, to determine the molecular basis for the neutralization capacity of BoNT anti-sera, and to use an inhalation mouse BoNT model to test the efficacy of BoNT vaccines and determine the role of BoNT dual-receptors in inhalation botulism. A high throughput screen will identify small molecule inhibitors of BoNT entry into neurons, while the molecular and cellular properties of BoNT binding to their dual-receptors will be determined. These biochemical, biophysical, and structural studies provide a framework for translational research to develop the current and future vaccines and therapies against botulism. The research team has a history of collaborative investigations and includes expertise in the analysis of the structural biology, biochemistry, and neurophysiology of BoNT action. The GLRCE BoNT Core Facility, the University of Chicago Rickett's Regional Biocontainment Laboratory, the Argonne Structural Biology Center, and the NMR Facility at MCW will be utilized to facilitate these studies. Determining the mechanism for BoNT intoxication of neurons provides basic information that can be translated into an optimal subunit BoNT vaccine, to develop strategies to neutralize BoNT intoxication, and to expand the use of BoNT in clinical therapies. This information is also applicable for the rapid response to the intentional release of BoNT serotype variants.

Public Health Relevance

The botulinum neurotoxins are the most toxic proteins for humans. This research project will develop vaccines and therapies to neutralize the botulinum neurotoxins and determine how these toxins paralyze humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057153-09
Application #
8376935
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$617,323
Indirect Cost
$113,859
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Le, J; Dam, Q; Schweizer, M et al. (2016) Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur J Clin Microbiol Infect Dis 35:1441-7
Agostoni, Marco; Waters, Christopher M; Montgomery, Beronda L (2016) Regulation of biofilm formation and cellular buoyancy through modulating intracellular cyclic di-GMP levels in engineered cyanobacteria. Biotechnol Bioeng 113:311-9
Duckworth, Benjamin P; Wilson, Daniel J; Aldrich, Courtney C (2016) Measurement of Nonribosomal Peptide Synthetase Adenylation Domain Activity Using a Continuous Hydroxylamine Release Assay. Methods Mol Biol 1401:53-61
Kuhn, Misty L; Alexander, Evan; Minasov, George et al. (2016) Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis. ACS Infect Dis 2:579-591
Hollands, Andrew; Corriden, Ross; Gysler, Gabriela et al. (2016) Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. J Biol Chem 291:13964-73
Park, Sung Ryeol; Tripathi, Ashootosh; Wu, Jianfeng et al. (2016) Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway. Nat Commun 7:10710
Hoang, Ky Van; Chen, Carolyn G; Koopman, Jacob et al. (2016) Identification of Genes Required for Secretion of the Francisella Oxidative Burst-Inhibiting Acid Phosphatase AcpA. Front Microbiol 7:605
Lin, Ann E; Beasley, Federico C; Olson, Joshua et al. (2015) Role of Hypoxia Inducible Factor-1α (HIF-1α) in Innate Defense against Uropathogenic Escherichia coli Infection. PLoS Pathog 11:e1004818
Becker, Russell E N; Bubeck Wardenburg, Juliane (2015) Staphylococcus aureus and the skin: a longstanding and complex interaction. Skinmed 13:111-9; quiz 120
Lopera, Juan G; Falendysz, Elizabeth A; Rocke, Tonie E et al. (2015) Attenuation of monkeypox virus by deletion of genomic regions. Virology 475:129-38

Showing the most recent 10 out of 505 publications