Abstract
Francisella tularensis is a facultative intracellular bacterium and the etiological agent of tularemia, a zoonotic disease. Infection of monocytic cells by F. tularensis can be controlled after activation with IFN-γ; however, the molecular mechanisms whereby the control is executed are incompletely understood. Recently, a key role has been attributed to the Guanylate-binding proteins (GBPs), interferon-inducible proteins involved in the cell-specific immunity against various intracellular pathogens. Here, we assessed the responses of bone marrow-derived murine macrophages (BMDM) and GBP-deficient BMDM to F. tularensis strains of variable virulence; the highly virulent SCHU S4 strain, the human live vaccine strain (LVS), or the widely used surrogate for F. tularensis, the low virulent F. novicida. Each of the strains multiplied rapidly in BMDM, but after addition of IFN-γ, significant GBP-dependent control of infection was observed for the LVS and F. novicida strains, whereas there was no control of the SCHU S4 infection. However, no differences in GBP transcription or translation were observed in the infected cell cultures. During co-infection with F. novicida and SCHU S4, significant control of both strains was observed. Patterns of 18 cytokines were very distinct between infected cell cultures and high levels were observed for almost all cytokines in F. novicida-infected cultures and very low levels in SCHU S4-infected cultures, whereas levels in co-infected cultures for a majority of cytokines showed intermediate levels, or levels similar to those of F. novicida-infected cultures. We conclude that the control of BMDM infection with F. tularensis LVS or F. novicida is GBP-dependent, whereas SCHU S4 was only controlled during co-infection. Since expression of GBP was similar regardless of infecting agent, the findings imply that SCHU S4 has an inherent ability to evade the GBP-dependent anti-bacterial mechanisms.
Highlights
Francisella tularensis is a highly virulent bacterium and the etiological agent of the zoonotic infection tularemia, a febrile disease affecting many mammalian species, including humans (Sjöstedt, 2007)
To assess the ability of F. tularensis strains to replicate intracellularly, bone marrow-derived murine macrophages (BMDM) were infected with F. novicida, live vaccine strain (LVS), or SCHU S4
In the presence of IFN-g, the increase was significantly lower for LVS and F. novicida, 1.2 log10 CFU and 0.2 log10 CFU (P < 0.01 and 0.001, respectively), respectively, whereas the number of SCHU S4 was not affected by IFN-g; a net Regulation of Guanylate-binding proteins (GBPs) During F. tularensis Infection
Summary
Francisella tularensis is a highly virulent bacterium and the etiological agent of the zoonotic infection tularemia, a febrile disease affecting many mammalian species, including humans (Sjöstedt, 2007). The highest virulence is exhibited by strains belonging to subspecies tularensis and they are confined to North America, whereas strains of subspecies holarctica have been isolated from many locations across the Northern hemisphere and exhibit lower virulence (Kingry and Petersen, 2014). F. novicida is an often used surrogate for F. tularensis, since it is genetically very closely related and even has been suggested to be designated as a subspecies (Kingry and Petersen, 2014). F. novicida is a very rare human pathogen and, compared to F. tularensis strains, demonstrates distinct biological features upon intracellular infection; most notably strong pro-inflammatory properties (Cowley and Elkins, 2011; Gillette et al, 2014)
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