Vaccines and therapies against botulism

肉毒杆菌中毒疫苗和疗法

• 批准号: 8448664
• 负责人: Joseph T Barbieri
• 金额: $ 77.91万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448664
• 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，已被归类为 疾病控制和预防中心的A类毒素。除了自然路线外， 中毒(食源性肉毒杆菌中毒、皮肤肉毒杆菌中毒和婴儿肉毒杆菌中毒)、吸入性肉毒杆菌中毒 建议作为恶意活动的传递机制。目前肉毒杆菌中毒的疫苗和治疗方法 对公众的供应是有限的。BNTs有七种血清型(称为A-G)，其基础是 交叉血清保护。作为原理的证明，一种亚单位疫苗被生产出来，以防止 被七种血清型的邦特所陶醉。该应用程序将继续开发疫苗和 针对肉毒杆菌中毒的治疗，并表征神经元上的BONT双受体。 这项应用的目的是优化亚单位BONT疫苗，中和七种血清型的 BONT，以确定一种新的BONT血清型，以确定中和的分子基础 BONT抗血清的能力，并使用吸入性小鼠BONT模型来测试BONT的效果 并确定BoNT双受体在吸入性肉毒杆菌中毒中的作用。高吞吐量的屏幕将 确定BONT进入神经元的小分子抑制剂，而BONT的分子和细胞特性 将确定BoNT与它们的双受体的结合。这些生化、生物物理和结构 研究为转化研究提供了一个框架，以开发当前和未来的疫苗和 肉毒杆菌中毒的治疗方法。 研究小组有合作调查的历史，并包括分析 BONT作用的结构生物学、生物化学和神经生理学。GLRCE BONT核心设施， 芝加哥大学里克特大学的区域生物遏制实验室，阿贡结构生物学中心， 并将利用MCW的核磁共振设施来促进这些研究。确定以下机制： 神经元的BONT中毒提供了可转化为最佳亚单位BONT的基本信息 疫苗，开发中和BONT中毒的策略，并扩大BONT在临床上的使用 治疗。这一信息也适用于对故意释放BONT的快速反应 血清型变异。