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.

其传播的便利性，被武器化的历史以及造成严重和致命的倾向