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Infect. Immun. doi:10.1128/IAI.01203-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Co-activating Signals for the Hepatic Lymphocyte Interferon- Response to Francisella tularensis

Department of Microbiology, Molecular Genetics, and Immunology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160

^* To whom correspondence should be addressed. Email: mparmely{at}kumc.edu.

	Abstract

The facultative intracellular bacterium Francisella tularensis is capable of causing systemic infections in various hosts, including mice and humans. The liver is a major secondary site of F. tularensis infection, but hepatic immune responses to the pathogen remain poorly defined. Immune protection against the pathogen is thought to depend on the cytokine interferon-gamma (IFN-), but the cellular basis for this response has not been characterized. Here we report that natural killer cells from the livers of naïve uninfected mice produced IFN- when challenged with live bacteria in vitro and that the responses were greatly increased by co-activation of the cells with either recombinant interleukin-12 or interleukin-18. Moreover, the two cytokines had strong synergistic effects on IFN- induction. Neutralizing antibodies to either IL-12 or IL-18 inhibited IFN- production in vitro, and mice deficient in the p35 subunit of IL-12 failed to show IFN- responses to bacterial challenge either in vitro or in vivo. Clinical isolates of highly virulent type A F. tularensis subsp. tularensis organisms were comparable to the attenuated live vaccine strain of F. tularensis subsp. holartica in their ability to induce IL-12 and IFN- expression. These findings demonstrate that cells capable of mounting IFN- responses to F. tularensis are resident within the livers of uninfected mice and depend upon co-activation by IL-12 and IL-18 for optimum responses.

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