宿主初始结核菌感染状态对重组ESAT-6亚单位疫苗诱导的特异性T细胞应答的影响及机制研究

About one-third of the world's population is infected with Mycobacterium tuberculosis. An effective vaccine capable of stopping the large population of individuals who harbor latent infection to develop active disease is critical component in any plan to eradicate tuberculosis. However because of lack of ideal model of latent TB, the impact of concurrent infection on effect and safety of the vaccine is not known. We have established a simple and controllable model of latent TB in mouse using a streptomycin(STR)-dependent Mycobacterium tuberculosis strain 18b. We found that: In the absence of streptomycin, the Mycobacterium survives but does not grow in the lung; If streptomycin is provided to the bacteria then it will proliferate in the lung. Consistent with this result, significant destructive pathology was found in the lung presence of streptomycin but no significant destructive pathology was seen absence of streptomycin. The antigen-specific CD4 T cell immune response is different between mice harboring growing bacteria to those in mice wherein the bacteria are not growing. Here we plan to determine the impact and mechanism of growing and latent bacteria on antigen-specific CD4 T cells immune responses using the established mouse model of latent TB and the ESAT-6 subunit vaccine which was validated can establish of protective responses during Mycobacterium tuberculosis challenge. These data will allow us to develop new vaccines capable of inducing protective T cells in the population of individuals who harbor latent infection.

全球约三分之一人口感染结核菌，研发针对这一庞大的结核菌潜伏感染人群的疫苗，阻止其进展活动性结核病，是实现根除结核病目标的关键；但由于缺乏理想的结核菌潜伏感染模型，目前尚不清楚初始结核菌感染对于疫苗的效果和安全性影响。利用链霉素依赖性结核菌株18b，我们建立了一个简单可控的结核菌潜伏感染小鼠模型：在无链霉素的情况下，感染的结核菌可在肺部存活但不增殖。而在链霉素存在情况下，结核菌则复制增殖。与此一致，不增殖细菌感染小鼠肺脏无明显病理损害，而增殖菌感染小鼠病理损害明显。免疫学分析，显示，两种细菌诱导的特异性CD4 T细胞免疫显著不同。本项目将利用上述潜伏感染小鼠模型，以前期已验证具有免疫保护效果的ESAT-6亚单位疫苗为工具，研究细菌复制状态对特异性CD4 T细胞免疫的影响及其具体的机制，从而为临床研发适用于潜伏感染人群的预防性疫苗提供科学依据和重要的临床前数据。