Vaccines and therapies against botulism

肉毒杆菌中毒疫苗和疗法

• 批准号: 8376935
• 负责人: Joseph T Barbieri
• 金额: $ 72.62万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376935
• 关键词: Basic Science; Binding; Biochemical; Biochemistry; Biological; Bontoxilysin; Botulinum Toxin Type A; Botulism; Breathing; CCRL2 gene; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Chicago; Clinical; Clostridial Neurotoxin; Complement; Core Facility; Cutaneous; Escherichia coli; Future; General Population; Human; Infantile Botulism; Intervention; Intoxication; Investigation; Laboratories; Modeling; Molecular; Mus; Neurons; Paralysed; Property; Proteins; Recording of previous events; Research; Research Project Grants; Role; Route; Serotyping; Serum; Solubility; Subunit Vaccines; Toxin; Translating; Translational Research; Universities; Vaccine Therapy; Vaccines; Variant; base; biodefense; botulinum toxin type B; disorder prevention; efficacy testing; foodborne; high throughput screening; inhibitor/antagonist; mouse model; neurophysiology; neurotoxin receptor; neutralizing vaccine; pathogen; receptor; receptor vaccine; research study; response; small molecule; structural biology; three dimensional structure; translational study

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.

肉毒杆菌神经毒素（BoNTs）是对人类毒性最大的蛋白质，已被分类为