Tularemia

它的传播容易、被武器化的历史以及导致严重和致命的倾向 吸入后的疾病，使弗朗西斯土拉氏杆菌(Ft)成为令人担忧的A类生物恐怖分子。 40年来唯一可用的疫苗是有效的，但其减毒模式尚不清楚，FDA 还没有批准它的普遍使用。新疫苗的开发受到信息匮乏的限制 该菌株的毒力决定因素。该项目将提供(1)延长无病间隔的措施 直到最终的治疗/疫苗被实施；以及(2)诱导体液和细胞的疫苗 对堡垒的免疫力。项目1A将描述不寻常的Ft内毒素诱导介体的机制 负责图拉热症的全身炎症反应，并确定试剂是否已经在 脓毒症的临床检测在治疗播散性图拉热症的小鼠模型中是有用的。vt.在.的基础上 在刺激下，T细胞迅速产生炎性细胞因子，这些细胞因子对初始的先天免疫至关重要 响应和适应性响应的组织。？8T细胞的激活与 图拉热症的恢复期。氨基双膦酸类药物，广泛用于骨病，刺激_/(5T) 细胞，并可作为暴露于Ft的个人的初步治疗(项目1B)。项目2将描述 Ft胶囊，并开发一种结合疫苗，使用B。 炭疽或源自鼠疫或福尔马林的蛋白质。快速提高天然免疫力的佐剂(如CpG) 可能会加速体液反应，并提供早期保护。比如针对细胞内的Vi疫苗 病原体伤寒沙门氏菌，Ft衣壳结合疫苗旨在防止Ft到达其 所需的细胞内生态位。对Ft的持久免疫需要细胞免疫反应。基于我们的 以前成功培育出活的减毒沙门氏菌菌株，我们将设计一种减毒，容易 接种Ft疫苗(项目3A)。标记签名的突变将定义额外的目标 毒力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最佳地传递预置效应器/记忆 T细胞到肺和肝脏，是Ft复制的部位。这些研究将为公共卫生官员提供短期 以及在堡垒发生生物恐怖袭击时的明确治疗选择。

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.