SALMONELLA VACCINES THAT DELIVER BOTH ANTIGEN & CYTOKINE

减毒沙门氏菌已被用作异源沙门氏菌的载体 用于人类和动物疫苗接种的抗原。在小鼠体内，鼠伤寒沙门氏菌通常 感染肠道Peyer‘s斑块中的巨噬细胞以及 肝和脾。我们将比较小鼠口服后的免疫反应- 接种了表达两种模式抗原之一的鼠伤寒沙门氏菌： (L)猴免疫缺陷病毒Gag蛋白(SIV Gag)和(2)B 志贺样毒素L亚基(SLT-L)及SLT-11亚基的研究 肠出血性大肠杆菌。其中一种菌株，旨在增强 对一种抗原的细胞免疫反应，会传递编码IL-1的DNA 2细胞因子和SIV Gag蛋白直接进入巨噬细胞，然后 适当地转录、翻译和处理这些蛋白质。去做 这样，沙门氏菌菌株将包含两组原核基因 在严格控制的启动子下，吞噬后会释放 细菌从吞噬小体进入巨噬细胞的细胞质，以及 然后2)裂解细菌，从而释放原核/真核生物 携带细胞因子和病毒DNA的穿梭载体进入细胞质 巨噬细胞。感染沙门氏菌携带者菌株的巨噬细胞 将处理抗原并共同表达特定的细胞因子，从而导致 具有针对性和特异性的增强免疫反应。其中之一 旨在增强粘膜免疫力的菌株将共同表达IL-5，a 增加SLGA产生的细胞因子，以及SLT保护性 抗原。最后，我们将使用沙门氏菌疫苗系统进行评估 对异种抗原产生的T细胞反应的类型 通过疫苗株直接传递到抗原的细胞质 呈现细胞。这些研究的结果直接应用于 有效疫苗的生产可以特别地调节 免疫系统对细胞内和 细胞外病原体。

Attenuated strains of Salmonella have been used as carriers of heterologous antigens for human and animal vaccination. in mice, S. typhimurium normally infects macrophages in the Peyer's patches of the gut and also cells of the liver and the spleen. We will compare the immune response of mice orally- inoculated with S. typhimurium which expresses one of two model antigens: (l) Simian immunodeficiency virus gag protein (SIV gag) and (2) the B subunits of Shiga-like toxin type l (SLT-l) and SLT-ll from Enterohemorragic E. coli. One of these strains, designed to enhance a cellular immune response to an antigen, will deliver DNA encoding the IL-1 2 cytokine and the SIV gag protein directly to macrophages which will then appropriately transcribe, translate, and process these proteins. To do this, the Salmonella strain will contain two sets of prokaryotic genes under a tightly regulated promoter that after phagocytosis will 1) liberate the bacteria from the phagosome into the cytoplasm of a macrophage, and then 2) lyse the bacterium thereby releasing a prokaryotic/eukaryotic shuttle vector carrying cytokine and viral DNA into the cytoplasm of the macrophage. Those macrophages infected with the Salmonella carrier strains will process the antigen and co-express specific cytokines thus resulting in a targeted and specific enhanced immune response. One of the other strains, designed to augment a mucosal immunity, will co-express IL-5, a cytokine that augments slgA production, together with the SLT protective antigens. finally, we will use the Salmonella vaccine system to evaluate the type of T cell response generated to a heterologous antigen that is delivered via a vaccine strain directly to the cytoplasm of an antigen presenting cell. The results from these studies have direct application to the production of effective vaccines that can specifically modulate the immune system to develop a protective response against intracellular and extracellular pathogens.