Anthrax

炭疽病

• 批准号: 7678783
• 负责人: ERIK L HEWLETT
• 金额: $ 51.16万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678783
• 关键词: Address; Animal Model; Anthrax Vaccines; Anthrax disease; Antigens; Attenuated; Bacillus anthracis; Bacillus anthracis spore; Bioterrorism; Biothrax; Blood Cells; Categories; Cells; Edema; Evaluation; Genes; Germination; Image; Immune response; Individual; Licensing; Life; Location; Molecular; Mucosal Immunity; Mus; Organism; Pathogenesis; Population; Process; Reagent; Recombinant Proteins; Recombinants; Reproduction spores; Research; Research Personnel; Role; Salmonella; Salmonella typhi; System; T-Lymphocyte; Testing; Toxin; Vaccines; Virulence Factors; anthrax lethal factor; base; capsule; experience; microbial; mouse model; novel strategies; novel vaccines; response; vaccine development; vector vaccine

Bacillus anthracis is a Gram-positive, spore-forming, Category A organism that has already been used as a weapon of bioterrorism in the US. Its principal virulence factors are two toxins, Lethal Toxin (LT) and Edema Toxin (ET) and an anti-phagocytic capsule. Although an efficacious vaccine (Biothrax), consisting primarily of Protective Antigen (PA), is licensed in the US, the need to immunize a large segment of the population on short notice in case of attack requires a new vaccine that is less reactogenic and able to elicit a rapid protective response. The objectives of this project are to identify new antigens from B. anthracis spores (Sub-Project I.1) and vegetative cells (Sub-Project 1.2) that can be included in a new anthrax vaccine. The genes for these antigens will be cloned, expressed as recombinant proteins and tested for protective activity. To understand better and visualize the process and location of germination, a new mouse model will be developed, using conditional expression of a lux gene in B. anthracis (Sub-Project I. 1). The host immune response to B. anthracis antigens, including the role of T cells and the importance of HLA type, will be characterized using blood/cells from subjects who have had anthrax or have been immunized with the vaccine (Sub-Project 1.2). Despite availability of new structural information on ET and LT, little is known about their cellular actions or roles in anthrax. These issues will be addressed in Sub-Project 1.3, by exploration of the intracellular consequences of ET and LT enzymatic activities, alone and together, and evaluation of reagents to block their effects. Finally, a novel strategy for anthrax immunity, the mucosal-prime/parenteral-boost paradigm using a Salmonella-based live vector vaccine, will be tested (Sub-Project 1.4). With this approach, the host system is primed with mucosally administered, attenuated S. Typhi expressing PA and/or other antigens from Sub-Projects I.1 and 1.2, so that the host response will be more vigorous to subsequent parenteral boosting with PA (Biothrax), recombinant PA, or PA conjugated to the other newly identified antigens from spores or vegetative cells [Sub- Projects 1.1 and 1.2]. This research will be carried out by a team of investigators who have extensive experience in microbial pathogenesis, antigen identification, animal models, toxin mechanisms, and vaccine development and testing. The deliverables include new antigens from B. anthracis, tested in murine and NHP systems, compounds with potential to impede or block the molecular mechanisms by which individuals die of anthrax, and a new mouse model for imaging germination and bacterial distribution.

炭疽芽孢杆菌是一种革兰氏阳性，形成孢子的类别，一种已经被用作的生物 在美国，生物恐怖主义的武器。它的主要毒力因子是两个毒素，致命的毒素（LT）和水肿 毒素（ET）和抗斑细胞囊。虽然是一种有效的疫苗（Biothrax），主要由 保护性抗原（PA）在美国获得许可，需要在短时间内接种大部分人口 请注意，如果攻击需要一种新的疫苗，该疫苗的反应源性较低并能够引起快速保护 回复。 该项目的目的是从炭疽芽孢杆菌孢子（subroject i.1）和 可以包含在新的炭疽疫苗中的营养细胞（亚物体1.2）。这些抗原的基因将 克隆，表示为重组蛋白，并测试了保护活性。更好地理解 可视化发芽的过程和位置，将开发一个新的鼠标模型，使用条件 lux基因在炭疽芽孢杆菌中的表达（subroject I. 1）。宿主对炭疽芽孢杆菌抗原的免疫反应， 包括T细胞的作用和HLA类型的重要性，将使用受试者的血液/细胞来表征 患有炭疽或已通过疫苗免疫的人（亚物体1.2）。 尽管有有关ET和LT的新结构信息的可用性，但对它们的细胞作用或 在炭疽中的角色。这些问题将通过探索细胞内解决。 ET和LT酶促活性的后果，单独，共同进行，并评估试剂以阻止其 效果。最后，一种新型的炭疽免疫策略 基于沙门氏菌的活载体疫苗将进行测试（亚物体1.4）。使用这种方法，主机系统是 用粘液施用的，减弱的链球菌表达PA和/或其他抗原。 i.1和1.2，以使宿主反应对随后的肠胃外（biothrax）的增强更为有力， 重组PA，或与来自孢子或营养细胞的其他新鉴定的抗原共轭的PA [ 项目1.1和1.2]。 这项研究将由一个在微生物方面拥有丰富经验的调查员团队进行 发病机理，抗原鉴定，动物模型，毒素机制以及疫苗的发育和测试。 可交付成果包括炭疽芽孢杆菌的新抗原，在鼠和NHP系统中测试 阻碍或阻止个体死于炭疽的分子机制的潜力，以及用于成像的新鼠标模型 发芽和细菌分布。