Characterization of rationally attenuated Francisella tularensis vaccine strains that harbor deletions in the guaA and guaB genes

Araceli E. Santiago, Leah E. Cole, Augusto Franco, Stefanie N. Vogel, Myron M. Levine, Eileen M. Barry

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Francisella tularensis, the etiologic agent of tularemia, can cause severe and fatal infection after inhalation of as few as 10-100 CFU. F. tularensis is a potential bioterrorism agent and, therefore, a priority for countermeasure development. Vaccination with the live vaccine strain (LVS), developed from a Type B strain, confers partial protection against aerosal exposure to the more virulent Type A strains and provides proof of principle that a live attenuated vaccine strain may be efficacious. However LVS suffers from several notable drawbacks that have prevented its licensure and widespread use. To address the specific deficiencies that render LVS a sub-optimal tularemia vaccine, we engineered F. tularensis LVS strains with targeted deletions in the guaA or guaB genes that encode critical enzymes in the guanine nucleotide biosynthetic pathway. F. tularensis LVSΔguaA and LVSΔguaB mutants were guanine auxotrophs and were highly attenuated in a mouse model of infection. While the mutants failed to replicate in macrophages, a robust proinflammatory cytokine response, equivalent to that of the parental LVS, was elicited. Mice vaccinated with a single dose of the F. tularensis LVSΔguaA or LVSΔguaB mutant were fully protected against subsequent lethal challenge with the LVS parental strain. These findings suggest the specific deletion of these target genes could generate a safe and efficacious live attenuated vaccine.

    Original languageEnglish (US)
    Pages (from-to)2426-2436
    Number of pages11
    JournalVaccine
    Volume27
    Issue number18
    DOIs
    StatePublished - Apr 21 2009

    Keywords

    • Francisella tularensis
    • LVS
    • Tularemia vaccine

    ASJC Scopus subject areas

    • Molecular Medicine
    • Immunology and Microbiology(all)
    • veterinary(all)
    • Public Health, Environmental and Occupational Health
    • Infectious Diseases

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