This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heath, L. Articles by Brieland, J. Search for Related Content PubMed PubMed Citation Articles by Heath, L. Articles by Brieland, J.

 Previous Article  |  Next Article 

Infect. Immun., Dec 1996, 5151-5160, Vol 64, No. 12
Copyright © 1996, American Society for Microbiology

Effector mechanisms responsible for gamma interferon-mediated host resistance to Legionella pneumophila lung infection: the role of endogenous nitric oxide differs in susceptible and resistant murine hosts

L Heath, C Chrisp, G Huffnagle, M LeGendre, Y Osawa, M Hurley, C Engleberg, J Fantone and J Brieland
Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor 48109-0614, USA.

To facilitate identification of the effector mechanism(s) responsible for gamma interferon (IFN-gamma)-mediated host resistance to Legionella pneumophila, a murine model of legionellosis in BALB/c mice with a targeted disruption in the IFN-gamma gene (gamma knockout [GKO] mice) was developed. Immunocompetent BALB/c mice and GKO mice were inoculated intratracheally with virulent L. pneumophila (10(6) bacteria per mouse), and bacterial clearance and the pulmonary inflammatory response were assessed. L. pneumophila did not replicate in, and was rapidly cleared from, the lungs of immunocompetent BALB/c mice, demonstrating that immunocompetent BALB/c mice are resistant to replicative L. pneumophila pulmonary infections. In contrast, similarly infected GKO mice developed persistent, replicative intrapulmonary L. pneumophila infections with extrapulmonary dissemination of the bacteria to the spleen. Histopathologic and flow cytometric analysis of L. pneumophila- infected lung tissue demonstrated that while immunocompetent BALB/c mice develop multifocal pneumonitis which resolves, similarly infected GKO mice develop diffuse pneumonitis with persistent neutrophil recruitment into the lung. Intratracheal administration of exogenous IFN-gamma to L. pneumophila-infected GKO mice facilitated intrapulmonary clearance of the bacteria, confirming the pivotal role of IFN-gamma in innate host defenses to L. pneumophila lung infection in this murine host. The potential role of endogenous reactive nitrogen intermediates, including nitric oxide (NO), in IFN-gamma-mediated resistance to L. pneumophila pulmonary infections in immunocompetent BALB/c mice was subsequently assessed. Macrophage inducible nitric oxide synthetase (an enzyme responsible for the production of NO) was induced in alveolar cells from L. pneumophila-infected immunocompetent BALB/c mice (with maximal expression at 48 h postinfection) but was not induced in similarly infected GKO mice. However, administration of the NO synthetase inhibitor N-monomethyl-L-arginine did not significantly inhibit clearance of L. pneumophila from the lung of immunocompetent BALB/c mice (compared with that in similarly infected mice not administered N-monomethyl-L-arginine). In contrast, we have previously demonstrated that IFN-gamma-induced host resistance to replicative L. pneumophila lung infections in a susceptible murine host (A/J mice) is mediated, in part, by endogenous NO. Taken together, these studies identify a differing role of endogenous NO in IFN-gamma-mediated resistance to L. pneumophila pulmonary infection in susceptible and resistant murine hosts.

This article has been cited by other articles:

• Bhan, U., Trujillo, G., Lyn-Kew, K., Newstead, M. W., Zeng, X., Hogaboam, C. M., Krieg, A. M., Standiford, T. J. (2008). Toll-Like Receptor 9 Regulates the Lung Macrophage Phenotype and Host Immunity in Murine Pneumonia Caused by Legionella pneumophila. Infect. Immun. 76: 2895-2904 [Abstract] [Full Text]  
• Santic, M., Molmeret, M., Abu Kwaik, Y. (2005). Maturation of the Legionella pneumophila-Containing Phagosome into a Phagolysosome within Gamma Interferon-Activated Macrophages. Infect. Immun. 73: 3166-3171 [Abstract] [Full Text]  
• Nagabhushanam, V., Solache, A., Ting, L.-M., Escaron, C. J., Zhang, J. Y., Ernst, J. D. (2003). Innate Inhibition of Adaptive Immunity: Mycobacterium tuberculosis-Induced IL-6 Inhibits Macrophage Responses to IFN-{gamma}. J. Immunol. 171: 4750-4757 [Abstract] [Full Text]  
• SHINOZAWA, Y., MATSUMOTO, T., UCHIDA, K., TSUJIMOTO, S., IWAKURA, Y., YAMAGUCHI, K. (2002). Role of interferon-gamma in inflammatory responses in murine respiratory infection with Legionella pneumophila. J Med Microbiol 51: 225-230 [Abstract] [Full Text]  
• Deng, J. C., Tateda, K., Zeng, X., Standiford, T. J. (2001). Transient Transgenic Expression of Gamma Interferon Promotes Legionella pneumophila Clearance in Immunocompetent Hosts. Infect. Immun. 69: 6382-6390 [Abstract] [Full Text]  
• Newton, C., McHugh, S., Widen, R., Nakachi, N., Klein, T., Friedman, H. (2000). Induction of Interleukin-4 (IL-4) by Legionella pneumophila Infection in BALB/c Mice and Regulation of Tumor Necrosis Factor Alpha, IL-6, and IL-1beta. Infect. Immun. 68: 5234-5240 [Abstract] [Full Text]  
• SINGH, S., WORT, S J., EVANS, T. W (1999). Inducible nitric oxide and pulmonary infection. Thorax 54: 959-960 [Full Text]  
• Sasaki, S., Miura, T., Nishikawa, S., Yamada, K., Hirasue, M., Nakane, A. (1998). Protective Role of Nitric Oxide in Staphylococcus aureus Infection in Mice. Infect. Immun. 66: 1017-1022 [Abstract] [Full Text]  
• Susa, M., Ticac, B., Rukavina, T., Doric, M., Marre, R. (1998). Legionella pneumophila Infection in Intratracheally Inoculated T Cell-Depleted or -Nondepleted A/J Mice. J. Immunol. 160: 316-321 [Abstract] [Full Text]