Typhus group rickettsial antigens recognized by CD8+ T lymphocytes

这项研究的长期目标是开发一种有效的预防两种斑疹伤寒的疫苗。 立克次体、伤寒立克次体和普氏立克次体。这些固有的胞内细菌分别是， 鼠斑疹伤寒和虱传流行性斑疹伤寒的代理人。后者是最严重的 已知的人类感染。这一特征加上普罗瓦泽克杆菌具有稳定传染性的事实， 可通过气雾剂传播，以前曾被武器化，证明有理由放置这个立克次体 在B类生物制剂中，精选药剂。疫苗的开发是可行的，因为天然的 立克次体感染提供了强大的保护性免疫；然而，目前还没有安全有效的疫苗 发展到目前为止。基于CD8+T细胞是免疫的基本效应细胞的知识 对抗立克次体，两个斑疹伤寒群立克次体的基因组几乎相同，我有 证明了远亲立克次体之间存在T细胞介导的交叉保护，即 假设CD8+T细胞识别的交叉反应斑疹伤寒群立克次体抗原将保护 用致死性立克次体DMA-Prime和重组痘苗-Boost方案免疫的小鼠 挑战。因此，该应用的目的是识别斑疹伤寒群立克次体交叉反应 保护性抗原。我将通过以下具体目标来实现这一目标：1)确定交叉反应 人和小鼠CD8+T细胞识别的斑疹伤寒群立克次体抗原；2)确定 立克次体DNA启动和立克次体重组病毒加强免疫所产生的保护 在小鼠模型中选择抗立克次体致死性攻击的抗原。我将通过以下方式实现这些目标： 1)通过激活抗立克次体CD8+T细胞效应器识别斑疹伤寒群立克次体抗原 通过暴露于感染了驱动表达的载体的抗原提呈细胞(APC)而发挥作用 以及2)检测所选抗原的免疫原性和效力 立克次体小鼠模型。这项研究对健康的影响是，它将确立最重要的 合理设计有效的立克次体疾病疫苗所需的知识，特别是 斑疹伤寒。

The long-term goal of this research is to develop an effective prophylactic vaccine against the two typhus group rickettsiae, Ricketisia typhi and R. prowazekii. These obligately intracellular bacteria are, respectively, the agents of murine typhus and louse-borne epidemic typhus. The latter is among the most severe of the known human infections. This characteristic together with the facts that R. prowazekii is stably infectious, transmissible by aerosol, and has been previously weaponized, justifies the placement of this Ricketisia among the category B biothreat select agents. The development of a vaccine is feasible because natural rickettsial infection provides strong protective immunity; however, no safe and effective vaccines have been developed thus far. Based on the knowledge that CD8+ T cells are fundamental effectors of immunity against rickettsiae, that the genomes of the two typhus group rickettsiae are almost identical, and that I have demonstrated that T cell-mediated cross-protection between distantly related rickettsiae occurs, I hypothesize that cross-reactive typhus group rickettsial antigens recognized by CD8+ T cells will protect mice immunized with a DMA-prime and recombinant vaccinia-boost protocol from a lethal rickettsial challenge. Thus, the objective of this application is to identify typhus group rickettsial cross-reactive protective antigens. I will approach this objective through the following specific aims: 1) identify crossreactive typhus group rickettsial antigens recognized by CD8+ T cells of mice and humans; and 2) determine the protection conferred by rickettsial DNA-priming and rickettsial recombinant viral boosting with the selected antigens against a lethal challenge with rickettsiae in a mouse model. I will carry out these aims by: 1) identifying typhus group rickettsial antigens through the activation of anti-rickettsia CD8+ Tcell effector functions by exposure to antigen presenting cells (APCs) transfected with a vector that drives the expression of rickettsial genes; and 2) testing the immunogenicity and efficacy of the selected antigens in appropriate rickettsial mouse models. The health impact of this research is that it will establish the most important knowledge necessary for the rational design of effective vaccines against rickettsial diseases, particularly typhus.