| Summary: | <i>Francisella tularensis</i> (<i>Ft</i>) 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 <i>Francisella</i> phagosomal transporter (<i>fpt</i>) 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 <i>fptA</i> and <i>fptF</i> genes in the C57BL/6J mouse model of respiratory tularemia. LVSΔ<i>fptA</i> and LVSΔ<i>fptF</i> were highly attenuated with LD<sub>50</sub> values of >20 times that of LVS when administered intranasally and conferred 100% protection against lethal challenge. Immune responses to the <i>fpt</i> 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 LVSΔ<i>fptA</i> and LVSΔf<i>ptF</i> 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 <i>Ft</i> and the modulation of the host immune response.
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