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    Deletion Mutants of Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal LVS Challenge in a Murine Model of Respiratory Tularemia

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    Author
    Hobbs, Brandi E
    Matson, Courtney A
    Theofilou, Vasileios I
    Webb, Tonya J
    Younis, Rania H
    Barry, Eileen M
    Date
    2021-06-24
    Journal
    Pathogens (Basel, Switzerland)
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/pathogens10070799
    Abstract
    Francisella tularensis (Ft) is a Gram-negative, facultative intracellular bacterium that is a Tier 1 Select Agent of concern for biodefense for which there is no licensed vaccine. A subfamily of 9 Francisella phagosomal transporter (fpt) genes belonging to the Major Facilitator Superfamily of transporters was identified as critical to pathogenesis and potential targets for attenuation and vaccine development. We evaluated the attenuation and protective capacity of LVS derivatives with deletions of the fptA and fptF genes in the C57BL/6J mouse model of respiratory tularemia. LVSΔfptA and LVSΔfptF were highly attenuated with LD50 values of >20 times that of LVS when administered intranasally and conferred 100% protection against lethal challenge. Immune responses to the fpt mutant strains in mouse lungs on day 6 post-infection were substantially modified compared to LVS and were associated with reduced organ burdens and reduced pathology. The immune responses to LVSΔfptA and LVSΔfptF were characterized by decreased levels of IL-10 and IL-1β in the BALF versus LVS, and increased numbers of B cells, αβ and γδ T cells, NK cells, and DCs versus LVS. These results support a fundamental requirement for FptA and FptF in the pathogenesis of Ft and the modulation of the host immune response.
    Keyword
    C57BL/6J mice
    Francisella tularensis
    Live Vaccine Strain (LVS)
    MFS transporter
    attenuation
    cytokines
    flow cytometry
    histopathology
    live attenuated vaccine
    organ burdens
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16199
    ae974a485f413a2113503eed53cd6c53
    10.3390/pathogens10070799
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