Abstract
Francisella tularensis is a highly infectious bacterial pathogen that causes the potentially fatal disease tularemia. The Live Vaccine Strain (LVS) of F. tularensis subsp. holarctica, while no longer licensed as a vaccine, is used as a model organism for identifying correlates of immunity and bacterial factors that mediate a productive immune response against F. tularensis. Recently, it was reported that two biovars of LVS differed in their virulence and vaccine efficacy. Genetic analysis showed that they differ in ferrous iron homeostasis; lower Fe2+ levels contributed to increased resistance to hydrogen peroxide in the vaccine efficacious LVS biovar. This also correlated with resistance to the bactericidal activity of interferon γ-stimulated murine bone marrow-derived macrophages. We have extended these findings further by showing that a mutant lacking bacterioferritin stimulates poor protection against Schu S4 challenge in a mouse model of tularemia. Together these results suggest that the efficacious biovar of LVS stimulates productive immunity by a mechanism that is dependent on its ability to limit the toxic effects of oxidative stress by maintaining optimally low levels of intracellular Fe2+.
Highlights
Francisella tularensis is a highly infectious bacterial pathogen that parasitizes the cytosol of host cells and causes the lethal disease tularemia in humans
We previously identified a F. tularensis gene involved in iron homeostasis from a mutagenesis screen to identify genes important for growth in human monocyte derived macrophages (MDMs)
While Live Vaccine Strain (LVS) is unlikely to be reapproved for human vaccination, it is used extensively as a standard by which other candidate Francisella vaccines can be measured in animal models, as well as a tool to discover correlates of immunity to F. tularensis
Summary
Francisella tularensis is a highly infectious bacterial pathogen that parasitizes the cytosol of host cells and causes the lethal disease tularemia in humans. Not available as a human vaccine, LVS is routinely used as a model to understand the genetic requirements of a F. tularensis strain to stimulate host immunity and as a tool to discover and characterize correlates of immunity in the host. Each of these areas of understanding are critical in the rational design of a future vaccine against virulent F. tularensis species
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