Tularemia

其传播的容易性、曾被武器化的历史以及造成严重和致命性的倾向 吸入后的疾病，使土拉热弗朗西斯菌（Ft）成为A类生物恐怖主义制剂的关注。 唯一一种有效期超过40年的疫苗是有效的，但其减毒模式尚不清楚，FDA 它没有被广泛使用。新疫苗的开发受到以下信息的缺乏的限制： Ft.本项目将提供（1）延长无病期的措施 直到最终的治疗/疫苗被实施;和（2）诱导体液和细胞免疫的疫苗， 免疫力，Ft。项目1A将描述不寻常的Ft LPS诱导介质的机制 负责土拉菌病的全身炎症反应，并确定试剂是否已经在 脓毒症的临床试验可用于治疗鼠模型中的播散性兔热病。后 刺激，？8 T细胞迅速产生炎症细胞因子，这些细胞因子对初始先天免疫和免疫应答都至关重要。 反应和组织的适应性反应。激活？8 T细胞与 从兔热病中恢复过来广泛用于骨疾病的氨基二膦酸类药物，刺激_/（5 T 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 以B的保护性抗原作为载体，研制了一种结合疫苗。 炭疽或来自鼠疫或Ft.也可快速增强先天免疫的佐剂（如CpG） 可以加速体液反应并提供早期保护。就像针对细胞内 伤寒沙门氏菌，Ft荚膜结合疫苗旨在防止Ft到达其 需要细胞内生态位。对Ft的持久免疫需要细胞免疫应答。基于我们 在开发沙门氏菌减毒活菌株的成功之前，我们将设计一种减毒的，容易 接种Ft疫苗（项目3A）。签名标记的诱变将定义额外的靶标， 减毒和新的毒力因子进行进一步研究（项目3C）。活化的T细胞被隔离在 外周组织我们将比较哪种免疫方案最佳地递送致敏效应子/记忆 T细胞转移到肺和肝，Ft复制的位点。这些研究将为公共卫生官员提供短期 和明确的治疗方案，在发生生物恐怖袭击的情况下与福特。

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.