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

项目概要/摘要（项目4，斯坦利） 结核分枝杆菌感染仍然是全世界死亡的主要原因。努力 由于缺乏有效的疫苗，防治结核病的工作受到阻碍。结核病疫苗和 其他需要基于细胞的免疫力来控制的细胞内病原体很难开发， 这是由于引发有效的基于细胞的免疫的佐剂的数量有限。我们最近报道说， 在蛋白质亚单位疫苗中配制的STING活化环二核苷酸（CDN）引起持久的免疫应答。 在小鼠模型中对结核分枝杆菌的保护性免疫。CDN佐剂的功效 当疫苗通过粘膜途径递送时，疫苗的免疫效果显著改善。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表征， 结核首先，我们将确定STING激活如何导致保护性免疫的发展， 使用基因敲除小鼠来剖析STING信号传导的不同输出的贡献。二是 发现CDN疫苗接种的功效依赖于IL-17，然而， IL-17的保护作用尚不清楚。我们将确定IL-17如何影响疫苗诱导的免疫反应。 这些指标包括IL-17应答、哪些CD 4 Th 17亚群是最重要的以及肺中哪些细胞类型对IL-17应答。 最后，我们在异源初免加强方案中测试CDN佐剂蛋白亚单位疫苗， 使用重组BCG和单核细胞增生李斯特菌菌株引发互补免疫应答 由考克斯（项目2）和波特诺伊（项目1）实验室开发。如果成功，这个项目将揭示新的 疫苗可以引起对结核病的保护性免疫的机制，并将利用这一知识来确定 增强效力的疫苗接种方案。

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.