STIMULATION OF CELLULAR IMMUNITY WITH ANTHRAX LETHAL TOXIN ANTIGEN FUSIONS

炭疽致死毒素抗原融合刺激细胞免疫

• 批准号: 2572391
• 负责人: K KLIMPEL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2572391
• 关键词: Bacillus; HIV envelope protein gp120; HIV envelope protein gp41; MHC class I antigen; T lymphocyte; bacterial antigens; bacterial proteins; bacterial toxins; bacterial vaccines; cellular immunity; cytoplasm; drug design /synthesis /production; human immunodeficiency virus 1; microorganism culture; posttranslational modifications; vaccine development; viral vaccines; virus antigen; virus protein

Bacillus anthracis secretes two toxins into the extracellular medium during growth. The two toxins consist of three distinct proteins which combine in a pairwise fashion. Protective antigen (PA) can combine with lethal factor (LF) or edema factor (EF). PA combined with LF makes lethal toxin while PA combined with EF makes edema toxin. Part of each toxin is directly transported to the cytosol of living cells where it exerts its effect (see Arora, N., K.R. Klimpel, Y. Singh, and S.H. Leppla, 1992, J Biol Chem 267:15542-15548). We propose to take advantage of the efficient delivery of proteins to the cytosol to intracellularly inoculate living cells. Nearly all cell types have the ability to process proteins found in the cytosol and combine them with MHC class I molecules. The combination of the processed protein with the MHC class I molecule presented on the surface of the living cell results in the stimulation of a population of T-cells which recognize the processed protein antigen. Once stimulated, this population of T-cells can expand and become primed to rapidly respond to and eliminate cells which bear an identical combination of MHC class I and processed antigen. By making fusions between LF and different polypeptide antigens we will be able to vaccinate a host against many pathogens. Our initial work will focus on priming a response against several known antigenic proteins expressed by HIV-1, including gp120, gp41 p24, Nef, Tat and Rev.

炭疽杆菌分泌两种毒素到细胞外介质中 在成长过程中。 这两种毒素由三种不同的蛋白质组成 其以成对方式组合联合收割机。 保护性抗原（PA）可 与致死因子（LF）或水肿因子（EF）联合收割机。 PA组合 LF与PA联合产生致命毒素，EF与PA联合产生水肿 毒素 每种毒素的一部分直接转运到细胞质中， 在其发挥作用的活细胞中（参见Arora，N.，K.R.克林佩尔， Y. Singh和S.H. Leppla，1992，J Biol Chem 267：15542-15548）。 我们 建议利用蛋白质的有效递送， 从胞质溶胶到胞内的活细胞。 几乎所有 细胞类型有能力处理细胞质中的蛋白质 并将它们与MHC I类分子联合收割机结合。 的组合 加工的蛋白质与MHC I类分子上提出的 活细胞的表面导致群体的刺激 识别加工蛋白抗原的T细胞。 一旦 在刺激下，这群T细胞可以扩增并启动， 快速反应并清除携带相同 MHC I类和加工抗原的组合。 通过融合 LF和不同的多肽抗原之间，我们将能够 给宿主接种疫苗以抵抗多种病原体。 我们最初的工作将集中在 引发对几种已知抗原蛋白的反应 HIV-1表达的蛋白质包括gp 120、gp 41、p24、Nef、达特和Rev.