Abstract
BackgroundFrancisella tularensis, a gram-negative bacterium replicates intracellularly within macrophages and efficiently evades the innate immune response. It is able to infect and replicate within Kupffer cells, specialized tissue macrophages of the liver, and to modulate the immune response upon infection to its own advantage. Studies on Francisella tularensis liver infection were mostly performed in animal models and difficult to extrapolate to the human situation, since human infections and clinical observations are rare.ResultsUsing a human co-culture model of macrophages and hepatocytes we investigated the course of infection of three Francisella tularensis strains (subspecies holarctica – wildtype and live vaccine strain, and mediasiatica - wildtype) and analyzed the immune response triggered upon infection. We observed that hepatocytes support the intracellular replication of Franciscella species in macrophages accompanied by a specific immune response inducing TNFα, IL-1β, IL-6 and fractalkine (CX3CL1) secretion and the induction of apoptosis.ConclusionsWe could demonstrate that this human macrophage / hepatocyte co-culture model reflects strain-specific virulence of Francisella tularensis. We developed a suitable tool for more detailed in vitro studies on the immune response upon liver cell infection by F. tularensis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-015-0621-3) contains supplementary material, which is available to authorized users.
Highlights
Francisella tularensis, a gram-negative bacterium replicates intracellularly within macrophages and efficiently evades the innate immune response
F. tularensis ssp. holarctica and live vaccine strain (LVS) strain were reliably detected in macrophages and hepatocytes
Presence and replication of intracellular viable bacteria in the hepatocyte / macrophages co-culture of all three F. tularensis strains were confirmed by colony forming unit (CFU) assays from lysates of infected cells (Fig. 1, Additional file 1: Figure S1)
Summary
Francisella tularensis, a gram-negative bacterium replicates intracellularly within macrophages and efficiently evades the innate immune response. Studies on Francisella tularensis liver infection were mostly performed in animal models and difficult to extrapolate to the human situation, since human infections and clinical observations are rare. F. tularensis primarily infects and persists in macrophages and is used as model bacterium to study adopted strategies to evade primary immune detection [3]. Tularensis is highly virulent in hares and the cause of Type A tularemia, whereas F. tularensis ssp. Holarctica is less virulent and causes Type B tularemia; F. tularensis subsp. Virulent and attenuated strains of F. tularensis, survive macrophage phagocytosis. They escape into the cytoplasm by preventing acidification and maturation of the phagosome [12,13,14]
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