Its ease of transmission, history of having been weaponized and propensity to cause severe and fataldisease 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 FDAhas not approved its general use. Development of new vaccines is limited by the paucity of information aboutthe virulence determinants of Ft. This project will provide (1) measures to extend the disease-free intervaluntil definitive therapy/vaccines are implemented; and (2) vaccines that induce humoral and cellularimmunity to Ft. Project 1A will characterize mechanisms by which the unusual Ft LPS induces mediatorsresponsible for the systemic inflammatory responses of tularemia, and determine if reagents already underclinical testing for sepsis are useful in the treatment of disseminated tularemia in a murine model. Uponstimulation, ?8 T cells rapidly produce inflammatory cytokines critical to both the initial innate immuneresponse and organization of the adaptive responses. Activation of ?8 T cells is associated withconvalescence from tularemia. Aminobisphosphonates drugs, widely used for bone disorders, stimulate _/(5Tcells and might serve as initial therapy for individuals exposed to Ft (Project 1B). Project 2 will characterizethe 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 intracellularpathogen, Salmonella Typhi, the Ft capsular conjugate vaccine is intended to prevent Ft from reaching itsrequired intracellular niche. Durable immunity to Ft requires a cellular immune response. Based on ourprevious success in developing live attenuated strains of Salmonella, we will design an attenuated, easilyadministered Ft vaccine (Project 3A). Signature-tagged mutagenesis will define additional targets forattenuation and new virulence factors for further study (Project 3C). Activated T cells are sequestered inperipheral tissues. We will compare which immunization regimen optimally delivers primed effector/memoryT cells to lung and liver, sites of Ft replication. These studies will provide public health officials short termand definitive treatment options in the event of a bioterror attack with Ft.
Showing the most recent 10 out of 375 publications
