Project 4: The intersection of innate and adaptive immunity to M. tuberculosis

项目摘要/摘要(项目4，Stanley) 结核分枝杆菌感染仍然是世界范围内的主要死亡原因。努力实现 由于缺乏有效的疫苗，与结核病大流行的斗争受到阻碍。结核分枝杆菌和结核分枝杆菌疫苗 在一定程度上，其他需要细胞免疫来控制的细胞内病原体很难培养出来。 由于诱导有效细胞免疫的佐剂数量有限。我们最近报道说， 蛋白质亚单位疫苗中的刺激性环二核苷酸(CDN)可诱导长效 在小鼠模型中对结核分枝杆菌的保护性免疫。CDN佐剂的疗效观察 当疫苗通过粘膜途径递送时，疫苗会得到显著改进。在此，我们建议 对CDN佐剂蛋白亚单位疫苗的免疫应答进行深入的表征 肺结核。首先，我们将确定刺痛激活如何导致保护性免疫的发展， 利用基因敲除小鼠来分析STING信号的不同输出的贡献。第二，我们有 发现CDN疫苗的效果依赖于IL-17，但背后的机制 IL-17的保护作用尚不清楚。我们将确定IL-17如何影响疫苗引发的免疫 反应，哪些CD4 Th17亚群是最重要的，以及肺中哪些细胞类型对IL-17有反应。 最后，我们测试了CDN佐剂蛋白亚单位疫苗在异种PRIME Boost方案中的设计 重组卡介苗和单核细胞增多性李斯特氏菌诱导的互补免疫应答 由考克斯(项目2)和波特诺伊(项目1)实验室开发。如果成功，这个项目将发现小说 疫苗可诱导对结核病的保护性免疫的机制，并将利用这一知识来识别 效力更高的疫苗接种方案。

Project Summary/Abstract (Project 4, Stanley) Infection with Mycobacterium tuberculosis continues to be a leading cause of death worldwide. Efforts to combat the tuberculosis pandemic are hampered by the lack of an effective vaccine. Vaccines against Mtb and other intracellular pathogens that require cell-based immunity for control have been difficult to develop, in part due to the limited number of adjuvants that elicit effective cell-based immunity. We recently reported that that STING-activating cyclic dinucleotides (CDNs) formulated in a protein subunit vaccine elicit long-lasting protective immunity to Mycobacterium tuberculosis in the mouse model. The efficacy of CDN adjuvanted vaccines is dramatically improved when the vaccine is delivered via a mucosal route. Here we propose to perform an in-depth characterization of the immune response to CDN adjuvanted protein subunit vaccines for tuberculosis. First, we will determine how STING activation results in the development of protective immunity, using knockout mice to dissect the contribution of the different outputs of STING signaling. Second, we have found that the efficacy of vaccination with CDN is dependent on IL-17, however the mechanisms underlying the protective efficacy of IL-17 are unknown. We will determine how IL-17 impacts the vaccine elicited immune response, which CD4 Th17 subsets are most important, and which cell types in the lung respond to IL-17. Finally, we test CDN adjuvanted protein subunit vaccines in heterologous prime boost regimens designed to elicit complementary immune responses using recombinant BCG and Listeria monocytogenes strains developed by the Cox (Project 2) and Portnoy (Project 1) labs. If successful, this project will uncover novel mechanisms by which vaccines can elicit protective immunity to TB, and will exploit this knowledge to identify vaccination regimens with enhanced efficacy.