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Abstract: Interactions between Francisella tularensis and the host are slowly being elucidated. Microarray technology was used to further characterise the response of Balb/c mice after inhalation of the virulent F. tularensis, SchuS4. The validated array data revealed changes in expression of 476 genes across a 96 h time course following infection (p ≤ 0.05). These data confirm down-regulation of the toll-like receptor pathway (TLR3, 4, 5, 7 and 8), and the induction of IFN-γ inducible genes (T-cell specific GTPase, β2 microglobulin and interleukin 21). The overall response appears to be two staged with an initial up-regulation of genes involved in apoptosis, TNFα production and antigen presentation. This is followed by a large alteration of expression at 96 h as the host succumbs to infection. A key regulatory time-point has been identified at 24 h post challenge, where several transcriptional events may predicate the progression of infection; these include transcriptional regulators of inflammation and proteolytic pathways. Pathway analysis indicates a novel role for cell–cell adhesion and extracellular matrix modulation in infection. Transcripts representing cellular junctions, focal adhesion and adherens junctions changed following infection. Additionally, aspects of extracellular matrix remodelling have been confirmed at the protein level, suggesting an important role of the respiratory epithelium in host response to F. tularensis warranting further study. [Copyright &y& Elsevier]

Abstract: Francisella tularensis is a category A select agent based on its infectivity and virulence but disease mechanisms in infection remain poorly understood. Murine pulmonary models of infection were therefore employed to assess and compare dissemination and pathology and to elucidate the host immune response to infection with the highly virulent Type A F. tularensis strain Schu4 versus the less virulent Type B live vaccine strain (LVS). We found that dissemination and pathology in the spleen was significantly greater in mice infected with F. tularensis Schu4 compared to mice infected with F. tularensis LVS. Using gene expression profiling to compare the response to infection with the two F. tularensis strains, we found that there were significant differences in the expression of genes involved in the apoptosis pathway, antigen processing and presentation pathways, and inflammatory response pathways in mice infected with Schu4 when compared to LVS. These transcriptional differences coincided with marked differences in dissemination and severity of organ lesions in mice infected with the Schu4 and LVS strains. Therefore, these findings indicate that altered apoptosis, antigen presentation and production of inflammatory mediators explain the differences in pathogenicity of F. tularensis Schu4 and LVS. [Copyright &y& Elsevier]

Abstract: Although survival of primary infection with the live vaccine strain (LVS) of Francisella tularensis depends on interferon gamma (IFN-γ), the relative importance of IFN-γ to secondary protective immunity in vivo has not been clearly established. Here we examine the role of IFN-γ in T cell priming and expression of vaccine-induced protection against lethal intraperitoneal challenge of mice. Large amounts of IFN-γ were detected between days 3 and 7 in the sera of LVS-immunized mice, while relatively small amounts were found transiently after secondary LVS challenge. Consistent with the production of this cytokine, mice lacking IFN-γ (gamma interferon knockout, GKO, mice) could not be successfully vaccinated with LVS or an attenuated mglA mutant of F. novicida to withstand secondary Francisella LVS challenge. Further, splenocytes from such primed mice did not adoptively transfer protection to naive GKO recipient mice in vivo, nor control the intramacrophage growth of LVS in vitro. Finally, LVS-immune WT mice depleted of IFN-γ prior to intraperitoneal challenge survived only the lowest doses of challenge. Thus successful priming of protective LVS-immune T cells, as well as complete expression of protection against Francisella during secondary challenge, depends heavily on IFN-γ. [Copyright &y& Elsevier]

Abstract: Concerns over weaponizable bacteria have recently prompted considerable interest in Francisella tularensis (Ft). In addition to its potential illicit use, Ft occurs naturally in diverse ecological niches including mammals, arthropods, and fresh water protozoans. Here we review the current knowledge of Ft adaptation which has ramifications for both basic and applied research. [Copyright &y& Elsevier]