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Infection and Immunity, October 2001, p. 6382-6390, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.6382-6390.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transient Transgenic Expression of Gamma Interferon Promotes Legionella pneumophila Clearance in Immunocompetent Hosts

Jane C. Deng,1 Kazuhiro Tateda,1,2 Xianying Zeng,1 and Theodore J. Standiford1,*

Department of Medicine, Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0360,1 and Department of Microbiology, Toho University School of Medicine, Tokyo 143-0015, Japan2

Received 21 March 2001/Returned for modification 24 May 2001/Accepted 7 July 2001

Gamma interferon (IFN-gamma ) and T1-phenotype immune responses are important components of host defense against a variety of intracellular pathogens, including Legionella pneumophila. The benefit of intrapulmonary adenovirus-mediated IFN-gamma gene therapy was investigated in a nonlethal murine model of experimental L. pneumophila pneumonia. Intratracheal (i.t.) administration of 106 CFU of L. pneumophila induced the expression of T1 phenotype cytokines, such as IFN-gamma and interleukin-12 (IL-12). Natural killer cells were identified as the major cellular source of IFN-gamma . To determine if enhanced expression of IFN-gamma in the lung could promote pulmonary clearance of L. pneumophila, we i.t. administered 5 × 108 PFU of a recombinant adenovirus vector containing the murine IFN-gamma cDNA (AdmIFN-gamma ) concomitant with L. pneumophila. We observed a 10-fold decrease in lung bacterial CFU at day 2 in the AdmIFN-gamma -treated group compared to controls (P < 0.01). Alveolar macrophages isolated from AdmIFN-gamma -treated animals displayed enhanced killing of intracellular L. pneumophila organisms ex vivo. Similar improvements in bacterial clearance were observed with i.t. recombinant IFN-gamma treatment. The transient transgenic expression of IL-12, a known inducer of IFN-gamma and promoter of T1-type immune responses, resulted in more modest improvement in bacterial clearance (sixfold reduction; P < 0.05). These results demonstrate that, even in immunocompetent hosts, exogenous administration or transient transgenic expression of IFN-gamma , and to a lesser extent IL-12, may be of potential therapeutic benefit in the treatment of patients with Legionella pneumonia.

* Corresponding author. Mailing address: The University of Michigan Medical Center, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, 6301 MSRBIII, Box 0642, Ann Arbor, MI 48109-0642. Phone: (734) 764-4554. Fax: (734) 764-4556. E-mail: tstandif{at}umich.edu.

Infection and Immunity, October 2001, p. 6382-6390, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.6382-6390.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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