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Infection and Immunity, March 2007, p. 1335-1342, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01203-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Coactivating Signals for the Hepatic Lymphocyte Gamma Interferon Response to Francisella tularensis{triangledown}

Jason R. Wickstrum,1 Kee-Jong Hong,1 Sirosh Bokhari,1 Natalie Reed,2 Nicholas McWilliams,1 Rebecca T. Horvat,2 and Michael J. Parmely1*

Department of Microbiology, Molecular Genetics, and Immunology,1 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 661602

Received 31 July 2006/ Returned for modification 6 September 2006/ Accepted 10 December 2006

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 gamma interferon (IFN-{gamma}), 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-{gamma} when challenged with live bacteria in vitro and that the responses were greatly increased by coactivation of the cells with either recombinant interleukin-12 (IL-12) or IL-18. Moreover, the two cytokines had strong synergistic effects on IFN-{gamma} induction. Neutralizing antibodies to either IL-12 or IL-18 inhibited IFN-{gamma} production in vitro, and mice deficient in the p35 subunit of IL-12 failed to show IFN-{gamma} responses to bacterial challenge either in vitro or in vivo. Clinical isolates of highly virulent type A Francisella tularensis subsp. tularensis organisms were comparable to the live attenuated vaccine strain of Francisella tularensis subsp. holarctica in their ability to induce IL-12 and IFN-{gamma} expression. These findings demonstrate that cells capable of mounting IFN-{gamma} responses to F. tularensis are resident within the livers of uninfected mice and depend on coactivation by IL-12 and IL-18 for optimum responses.

* Corresponding author. Mailing address: Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160. Phone: (913) 588-7053. Fax: (913) 588-7295. E-mail: mparmely{at}kumc.edu.

{triangledown} Published ahead of print on 18 December 2006.

Editor: J. L. Flynn

Infection and Immunity, March 2007, p. 1335-1342, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01203-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wickstrum, J. R., Bokhari, S. M., Fischer, J. L., Pinson, D. M., Yeh, H.-W., Horvat, R. T., Parmely, M. J. (2009). Francisella tularensis Induces Extensive Caspase-3 Activation and Apoptotic Cell Death in the Tissues of Infected Mice. Infect. Immun. 77: 4827-4836 [Abstract] [Full Text]  
  • Collazo, C. M., Meierovics, A. I., De Pascalis, R., Wu, T. H., Lyons, C. R., Elkins, K. L. (2009). T Cells from Lungs and Livers of Francisella tularensis-Immune Mice Control the Growth of Intracellular Bacteria. Infect. Immun. 77: 2010-2021 [Abstract] [Full Text]  
  • De Pascalis, R., Taylor, B. C., Elkins, K. L. (2008). Diverse Myeloid and Lymphoid Cell Subpopulations Produce Gamma Interferon during Early Innate Immune Responses to Francisella tularensis Live Vaccine Strain. Infect. Immun. 76: 4311-4321 [Abstract] [Full Text]  
  • Bokhari, S. M., Kim, K.-J., Pinson, D. M., Slusser, J., Yeh, H.-W., Parmely, M. J. (2008). NK Cells and Gamma Interferon Coordinate the Formation and Function of Hepatic Granulomas in Mice Infected with the Francisella tularensis Live Vaccine Strain. Infect. Immun. 76: 1379-1389 [Abstract] [Full Text]  
  • Hong, K.-J., Wickstrum, J. R., Yeh, H.-W., Parmely, M. J. (2007). Toll-Like Receptor 2 Controls the Gamma Interferon Response to Francisella tularensis by Mouse Liver Lymphocytes. Infect. Immun. 75: 5338-5345 [Abstract] [Full Text]  


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