Tuberculosis Vaccine Strategy Using Salmonella Vectors

该候选人正在申请职业发展奖，以便获得疫苗研究方面的额外培训。他将在Josephine Clark-Curtiss博士的实验室工作，Roy Curtiss博士是他的共同导师。这些实验室的合作研究环境应该为候选人提供一个理想的环境，以扩展他以前在结核病疫苗开发方面的研究经验。这些实验室的几名研究人员正在研究分枝杆菌遗传学和开发针对其他细菌性病原体的疫苗。在获奖期间，候选人将使用沙门氏菌活疫苗系统将特异性分枝杆菌多肽表位传递到抗原呈递细胞的细胞质中，以刺激MHC i类限制性CD8+ T细胞对这些抗原的反应。越来越多的证据表明CD8+ T细胞在对结核病的自然免疫中起作用。这一假设表明，旨在刺激CD8+ T细胞反应系统的疫苗策略可能会在结核病疫苗技术上取得进展。此外，这些进展可能对针对其他细胞内病原体的疫苗产生影响。本建议的目标是：(1)测试基于SptP或沙门氏菌分泌和易位的其他蛋白的重组蛋白刺激CD8+ T细胞对ESAT-6的反应的能力；(Z)测试诱导的ESAT-6特异性T细胞杀死细胞内分枝杆菌的能力；(3)测试重组SptP/ESAT-6表达的能力。减毒鼠伤寒沙门菌疫苗菌株保护小鼠免受毒力强的热支原体菌株的气溶胶攻击，以及(4)筛选可在该抗原呈递系统中作为备选疫苗候选物的其他分枝杆菌抗原。

The candidate is applying for a Career Development Award in order to gain additional training in vaccine research. He will work in Dr. Josephine Clark-Curtiss' lab, with Dr. Roy Curtiss serving as a co- mentor. The collaborative research environment of these laboratories should provide an ideal setting for the candidate to extend his previous research experience toward tuberculosis vaccine development. Several investigators in these laboratories are working on mycobacterial genetics and on the development of vaccines for other bacterial pathogens. During the award period the candidate will use a Salmonella live vaccine system to deliver specific mycobacterial polypeptide epitopes to the cytoplasm of antigen presenting cells, in order to stimulate an MHC class I-restricted CD8+ T cell response to these antigens. Growing evidence suggests a role for CD8+ T cells in natural immunity to tuberculosis. This hypothesis suggests that vaccine strategies designed to stimulate a CD8+ T cell response system may yield advances in tuberculosis vaccine technology. In addition, such advances may have implications for vaccines against other intracellular pathogens. The goals of this proposal are to: (1) test the ability of recombinant proteins based on SptP, or other proteins secreted and translocated by Salmonella, to stimulate a CD8+ T cell response to ESAT-6, (Z) test the ability of the elicited ESAT-6- specific T cells to kill intracellular mycobacteria, (3) test the ability of the recombinant SptP/ESAT-6-expressing, attenuated Salmonella typhimurium vaccine strain to protect mice from an aerosol challenge with a virulent Mycohac(erium (ttherculosis strain and (4) screen for additional mycobacterial antigens that could serve as alternative vaccine candidates in this antigen presentation system.