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
Author
Hobbs, Brandi EMatson, Courtney A
Theofilou, Vasileios I
Webb, Tonya J
Younis, Rania H
Barry, Eileen M
Date
2021-06-24Journal
Pathogens (Basel, Switzerland)Publisher
MDPI AGType
Article
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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 miceFrancisella tularensis
Live Vaccine Strain (LVS)
MFS transporter
attenuation
cytokines
flow cytometry
histopathology
live attenuated vaccine
organ burdens
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http://hdl.handle.net/10713/16199ae974a485f413a2113503eed53cd6c53
10.3390/pathogens10070799
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