Typhus group rickettsial antigens recognized by CD8+ T lymphocytes

本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 群立克次体、伤寒立克次体和R. prowazekii。这些专性胞内细菌分别是， 鼠斑疹伤寒和虱传流行性斑疹伤寒的病原体。后者是最严重的。 已知的人类感染。这一特性与R.普氏杆菌具有稳定的感染性， 可通过气溶胶传播，并且以前已被武器化，证明将这种立克次体 在B类生物威胁选择代理人。疫苗的开发是可行的，因为自然 立克次体感染提供了强大的保护性免疫力;然而，还没有安全有效的疫苗， 发展至今。基于CD 8 + T细胞是免疫的基本效应子的知识， 两个斑疹伤寒群立克次体的基因组几乎是相同的，我有 证明了T细胞介导的交叉保护在远亲立克次体之间发生， 假设由CD 8 + T细胞识别的交叉反应性斑疹伤寒群立克次体抗原将保护 用来自致死性立克次体的DMA-初免和重组牛痘-加强方案免疫小鼠 挑战.因此，本申请的目的是确定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）识别交叉反应 由小鼠和人的CD 8 + T细胞识别的斑疹伤寒组立克次体抗原;和2）确定 立克次体DNA引发和立克次体重组病毒加强所赋予的保护作用 在小鼠模型中对抗立克次体致死性攻击的选定抗原。我将通过以下方式实现这些目标： 1)通过激活抗立克次体CD 8 + T细胞效应子鉴定斑疹伤寒群立克次体抗原 通过暴露于用驱动表达的载体转染的抗原呈递细胞（APC）来发挥功能 立克次体基因的免疫原性和有效性; 2）在适当的条件下测试所选抗原的免疫原性和有效性。 立克次体小鼠模型。这项研究对健康的影响是，它将建立最重要的 合理设计有效的立克次体病疫苗所需的知识，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.