Tularemia

兔热病

• 批准号: 7678793
• 负责人: Alan S. Cross
• 金额: $ 35.32万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678793
• 关键词: Adjuvant; Animals; Anthrax disease; Antigens; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Bacillus anthracis; Bioterrorism; Bone Diseases; Breathing; Categories; Cells; Cellular Immunity; Conjugate Vaccines; Convalescence; Development; Disease; Event; Francisella tularensis; Genes; Goals; Host Defense; Immune; Immune response; Immunity; Immunization; Immunization Schedule; Individual; Infection; Inflammatory; Inflammatory Response; Intervention; Life; Lipopolysaccharides; Liver; Lung; Measures; Mediator of activation protein; Modeling; Mus; Mutagenesis; Natural Immunity; Oligonucleotides; Organism; Peripheral; Pharmaceutical Preparations; Plague; Play; Prevention; Prophylactic treatment; Proteins; Public Health; Range; Reagent; Recording of previous events; Role; Route; Salmonella; Salmonella typhi; Sepsis; Site; Symptoms; T memory cell; T-Lymphocyte; Tissues; Treatment Protocols; Tularemia; Typhoid Vaccine; United States Food and Drug Administration; Vaccine Therapy; Vaccines; Virulence; Virulence Factors; attenuation; base; capsule; cytokine; design; experience; improved; monophosphoryl lipid A; novel vaccines; pathogen; prevent; research clinical testing; response; success; trafficking; transmission process; vaccine development; vector vaccine

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.

它的易于传播，被武器化的历史以及造成严重和致命的倾向 吸入后的疾病，使弗朗西斯菌（Francisella tularensis）（FT）成为一个生物恐怖主义的类别。 唯一可用> 40年的疫苗是有效的，但其衰减方式尚不清楚，FDA 尚未批准其一般用途。新疫苗的开发受到有关信息的限制 ft的毒力决定因素。该项目将提供（1）扩展无病间隔的措施 直到实施确定的治疗/疫苗为止； （2）诱导体液和细胞的疫苗 对英尺的免疫力。项目1a将表征不寻常的FT LP诱导调解人的机制 负责Tularemia的系统性炎症反应，并确定试剂是否已经存在 败血症的临床测试可用于治疗鼠模型中的传播性肿瘤。之上 刺激，8个T细胞迅速产生对两种初始先天免疫至关重要的炎性细胞因子 自适应反应的反应和组织。 8 t细胞的激活与 康复来自Tularemia。广泛用于骨骼疾病的氨基异磷酸药物刺激_/（5T 细胞，可以作为暴露于FT的个体（项目1B）的初始治疗。项目2将描述 FT胶囊并开发共轭疫苗，用作B的保护性抗原。 源自鼠疫或ft的炭疽病或蛋白质。也迅速增强先天免疫力的佐剂（例如CpG） 可能会加快体液反应并提供早期保护。像细胞内的VI疫苗 病原体，沙门氏菌鼠伤寒，FT囊膜结合疫苗旨在防止FT到达其 需要细胞内小众。耐用的FT免疫需要细胞免疫反应。基于我们 以前在开发现场衰减的沙门氏菌菌株方面取得了成功，我们将设计一个衰减，轻松的 管理FT疫苗（项目3A）。签名标签的诱变将定义 进一步研究的衰减和新的毒力因素（项目3C）。活化的T细胞被隔离 外围组织。我们将比较哪种免疫方案最佳提供启动效应子/内存 T细胞到肺和肝脏，FT复制部位。这些研究将为公共卫生官员短期提供 如果有生物疗法攻击FT，则确定的治疗方案。