Vaccines and therapies against botulism

肉毒杆菌中毒疫苗和疗法

• 批准号: 7671968
• 负责人: Joseph T Barbieri
• 金额: $ 67.19万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-24 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671968
• 关键词: A Mouse; Address; Affinity; Basic Science; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Bontoxilysin; Botulinum Toxin Type A; Botulism; Breathing; CCRL2 gene; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Chicago; Clinical; Clostridial Neurotoxin; Complement; Complex; Core Facility; Cutaneous; Escherichia coli; Future; Gangliosides; General Population; Human; Immune response; Immunization; Infantile Botulism; Intervention; Intoxication; Investigation; Kinetics; Laboratories; Lipid Binding; Modeling; Molecular; Mus; Neurons; Paralysed; Property; Proteins; Recombinants; Recording of previous events; Research; Research Project Grants; Role; Route; Serotyping; Serum; Solubility; Specificity; Structure; Subunit Vaccines; Surface Plasmon Resonance; Therapeutic; Toxin; Translating; Translational Research; Universities; Vaccine Therapy; Vaccines; Variant; base; biodefense; botulinum toxin type B; efficacy testing; foodborne; high throughput screening; inhibitor/antagonist; mouse model; neurophysiology; neurotoxin receptor; neutralizing antibody; neutralizing vaccine; pathogen; prototype; receptor; research study; response; small molecule; structural biology; three dimensional structure; translational study; vaccine candidate

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 (BoNT) 是对人类毒性最强的蛋白质，已被归类为 疾病控制和预防中心确定的 A 类毒素。除了自然路线 中毒（食源性肉毒中毒、皮肤肉毒中毒和婴儿肉毒中毒）、吸入性肉毒中毒 被提议作为恶意活动的传递机制。目前针对肉毒杆菌中毒的疫苗和疗法 对公众的供应有限。 BoNT 有七种血清型（称为 A-G），基于 交叉血清保护。作为原理证明，生产了一种亚单位疫苗，可以预防 七种 BoNT 血清型中毒。该应用程序将继续开发疫苗和 针对肉毒杆菌中毒的疗法并表征神经元上的 BoNT 双受体。 该应用的目的是优化亚单位 BoNT 疫苗，以中和七种血清型 BoNT，表征“新”BoNT 血清型，确定中和的分子基础 BoNT抗血清的能力，并使用吸入小鼠BoNT模型来测试BoNT的功效 疫苗并确定 BoNT 双受体在吸入性肉毒中毒中的作用。高通量筛选将 鉴定 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 与其双受体的结合。这些生物化学、生物物理和结构 研究为开发当前和未来的疫苗和转化研究提供了框架 对抗肉毒杆菌中毒的疗法。 该研究团队有着合作调查的历史，并拥有分析问题的专业知识。 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 Rickett 地区生物防护实验室、阿贡结构生物学中心、 MCW 的 NMR 设施将用于促进这些研究。确定机制 神经元的 BoNT 中毒提供了可转化为最佳 BoNT 亚基的基本信息 疫苗，制定中和 BoNT 中毒的策略，并扩大 BoNT 在临床中的使用 疗法。此信息也适用于对 BoNT 有意释放的快速反应 血清型变异体。