Tularemia

它易于传播、被武器化的历史以及造成严重和致命的倾向 吸入后引起的疾病，使土拉弗朗西斯菌 (Ft) 成为令人关注的 A 类生物恐怖主义制剂。 唯一可用超过 40 年的疫苗是有效的，但其减毒模式尚不清楚，FDA 尚未批准其一般用途。新疫苗的开发因缺乏相关信息而受到限制 《金融时报》的毒力决定因素。本项目将提供（1）延长无病间隔的措施 直到实施明确的治疗/疫苗； (2) 诱导体液和细胞免疫的疫苗 对英尺的免疫力。项目 1A 将描述不寻常的 Ft LPS 诱导介质的机制 负责兔热病的全身炎症反应，并确定试剂是否已经在 败血症的临床测试可用于治疗小鼠模型中的播散性兔热病。之上 刺激后，?8 T 细胞迅速产生对初始先天免疫至关重要的炎症细胞因子 响应和适应性响应的组织。 ?8 T 细胞的激活与 兔热病康复期。氨基二磷酸盐药物，广泛用于骨疾病，刺激 _/(5T 细胞，并可能作为暴露于 Ft 的个体的初始治疗（项目 1B）。项目2将描述 Ft 胶囊并开发一种结合疫苗，使用 B. 炭疽病或源自鼠疫或英国《金融时报》的蛋白质。也能快速增强先天免疫的佐剂（例如 CpG） 可以加速体液反应并提供早期保护。就像细胞内疫苗 Vi 一样 Ft 荚膜结合疫苗旨在防止 Ft 达到其病原体，伤寒沙门氏菌 需要细胞内生态位。对 Ft 的持久免疫需要细胞免疫反应。基于我们的 继之前成功开发沙门氏菌减毒活菌株后，我们将设计一种易于使用的减毒菌株 注射 Ft 疫苗（项目 3A）。签名标记的诱变将定义额外的目标 减毒和新的毒力因子有待进一步研究（项目 3C）。活化的 T 细胞被隔离在 周围组织。我们将比较哪种免疫方案能够最佳地提供启动效应/记忆 T 细胞到达肺和肝，Ft 复制的位点。这些研究将为公共卫生官员提供短期 以及发生生物恐怖袭击时的明确治疗方案。

Its ease of transmission, history of having been weaponized and propensity to cause severe and fatal disease following inhalation, make Francisella tularensis (Ft) a Category A bioterrorism agent of concern. The only vaccine available for >40 years is efficacious, but its mode of attenuation is unknown and the FDA has not approved its general use. Development of new vaccines is limited by the paucity of information about the virulence determinants of Ft. This project will provide (1) measures to extend the disease-free interval until definitive therapy/vaccines are implemented; and (2) vaccines that induce humoral and cellular immunity to Ft. Project 1A will characterize mechanisms by which the unusual Ft LPS induces mediators responsible for the systemic inflammatory responses of tularemia, and determine if reagents already under clinical testing for sepsis are useful in the treatment of disseminated tularemia in a murine model. Upon stimulation, ?8 T cells rapidly produce inflammatory cytokines critical to both the initial innate immune response and organization of the adaptive responses. Activation of ?8 T cells is associated with convalescence from tularemia. Aminobisphosphonates drugs, widely used for bone disorders, stimulate _/(5T cells and might serve as initial therapy for individuals exposed to Ft (Project 1B). Project 2 will characterize the Ft capsule and develop a conjugate vaccine, using as carriers either the protective antigen of B. anthracis or proteins derived from plague or Ft. Adjuvants that also rapidly boost innate immunity (e.g. CpG) may accelerate a humoral response and provide early protection. Like the Vi vaccine for the intracellular pathogen, Salmonella Typhi, the Ft capsular conjugate vaccine is intended to prevent Ft from reaching its required intracellular niche. Durable immunity to Ft requires a cellular immune response. Based on our previous success in developing live attenuated strains of Salmonella, we will design an attenuated, easily administered Ft vaccine (Project 3A). Signature-tagged mutagenesis will define additional targets for attenuation and new virulence factors for further study (Project 3C). Activated T cells are sequestered in peripheral tissues. We will compare which immunization regimen optimally delivers primed effector/memory T cells to lung and liver, sites of Ft replication. These studies will provide public health officials short term and definitive treatment options in the event of a bioterror attack with Ft.