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.
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.
|Schuld, Nathan J; Vervacke, Jeffrey S; Lorimer, Ellen L et al. (2014) The chaperone protein SmgGDS interacts with small GTPases entering the prenylation pathway by recognizing the last amino acid in the CAAX motif. J Biol Chem 289:6862-76|
|Sharma, Preeti; Wang, Ningyan; Kranz, David M (2014) Soluble T cell receptor V? domains engineered for high-affinity binding to staphylococcal or streptococcal superantigens. Toxins (Basel) 6:556-74|
|Pensinger, Daniel A; Aliota, Matthew T; Schaenzer, Adam J et al. (2014) Selective pharmacologic inhibition of a PASTA kinase increases Listeria monocytogenes susceptibility to ?-lactam antibiotics. Antimicrob Agents Chemother 58:4486-94|
|Becker, Russell E N; Berube, Bryan J; Sampedro, Georgia R et al. (2014) Tissue-specific patterning of host innate immune responses by Staphylococcus aureus ?-toxin. J Innate Immun 6:619-31|
|Schiano, Chelsea A; Koo, Jovanka T; Schipma, Matthew J et al. (2014) Genome-wide analysis of small RNAs expressed by Yersinia pestis identifies a regulator of the Yop-Ysc type III secretion system. J Bacteriol 196:1659-70|
|Stach, Christopher S; Herrera, Alfa; Schlievert, Patrick M (2014) Staphylococcal superantigens interact with multiple host receptors to cause serious diseases. Immunol Res 59:177-81|
|Lifshitz, Ziv; Burstein, David; Schwartz, Kierstyn et al. (2014) Identification of novel Coxiella burnetii Icm/Dot effectors and genetic analysis of their involvement in modulating a mitogen-activated protein kinase pathway. Infect Immun 82:3740-52|
|Merriman, Joseph A; Nemeth, Kimberly A; Schlievert, Patrick M (2014) Novel antimicrobial peptides that inhibit gram positive bacterial exotoxin synthesis. PLoS One 9:e95661|
|Schneewind, Olaf; Missiakas, Dominique (2014) Genetic manipulation of Staphylococcus aureus. Curr Protoc Microbiol 32:Unit 9C.3.|
|Wang, Ya-Ting; Missiakas, Dominique; Schneewind, Olaf (2014) GneZ, a UDP-GlcNAc 2-epimerase, is required for S-layer assembly and vegetative growth of Bacillus anthracis. J Bacteriol 196:2969-78|
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