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.
Highlights
Francisella tularensis (Ft) is a Gram-negative, facultative intracellular, coccobacillus responsible for the zoonosis tularemia [1]
Live Vaccine Strain” (LVS) was extensively studied in volunteers where it demonstrated incomplete protection against aerosol challenge with the virulent Type A SchuS4 strain
While great effort has been placed on developing alternative vaccines, it is generally accepted that any new vaccine candidate needs to outperform LVS in terms of safety, immunogenicity, and protective efficacy against aerosolized Type A Ft
Summary
Francisella tularensis (Ft) is a Gram-negative, facultative intracellular, coccobacillus responsible for the zoonosis tularemia [1]. Mouse lungs infected with the LVS∆fptF mutant showed the least pathology when compared to the levels of tissue destruction caused by LVS, followed by LVS∆fptA These histopathology Pathogens 2021, 10, x FOR PEER RErVeIsEuWlts are consistent with their respective levels of attenuation (Table 1) which co8nofif r2m5 s that virulence is linked to the inflammatory response. Among the non-B and non-T cell populations, the numbers of neutrophils (Figure 6B) and non-B Class II+ cells (Figure 6C) were increased in LVS- and fpt mutant-infected versus mock-infected lungs; while not significant, there was a gradient of neutrophil influx where LVS induced the most neutrophils, followed by LVS∆fptA and LVS∆fptF, which corresponds to the histopathology data (Figure 3, Table 2). While great effort has been placed on developing alternative vaccines, it is generally accepted that any new vaccine candidate needs to outperform LVS in terms of safety, immunogenicity, and protective efficacy against aerosolized Type A Ft
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