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Infection and Immunity, June 2005, p. 3609-3617, Vol. 73, No. 6
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.6.3609-3617.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activity of Murine Lung Cells against Staphylococcus aureus Is Increased In Vitro and In Vivo after Elafin Gene Transfer

J. W. McMichael,1,{dagger} A. I. Maxwell,2,{dagger} K. Hayashi,1 K. Taylor,2 W. A. Wallace,3 J. R. Govan,4 J. R. Dorin,2 and J.-M. Sallenave1*

Rayne Laboratory, MRC Centre for Inflammation Research, Edinburgh University Medical School,1 MRC Human Genetics Unit, Western General Hospital,2 Directorate of Pathology, Royal Infirmary of Edinburgh,3 Cystic Fibrosis Microbiology Laboratory and Strain Repository, Medical Microbiology Division, Edinburgh University Medical School, Edinburgh, United Kingdom4

Received 9 November 2004/ Returned for modification 5 January 2005/ Accepted 19 January 2005

Staphylococcus aureus is a pathogen often found in pneumonia and sepsis. In the context of the resistance of this organism to conventional antibiotics, an understanding of the regulation of natural endogenous antimicrobial molecules is of paramount importance. Previous studies have shown that both human and mouse airways express a variety of these molecules, including defensins, cathelicidins, and the four-disulfide core protein secretory leukocyte protease inhibitor. We demonstrate here by culturing mouse tracheal epithelial cells at an air-liquid interface that, despite the production of Defb1, Defb14, and Defr1 in this system, these cells are unable to clear S. aureus when exposed to this respiratory pathogen. Using an adenovirus (Ad)-mediated gene transfer strategy, we show that overexpression of elafin, an anti-elastase/antimicrobial molecule (also a member of the four-disulfide core protein family), dramatically improves the clearance of S. aureus. In addition, we also demonstrate that this overexpression is efficient in vivo and that intratracheal instillation of Ad-elafin significantly reduced the lung bacterial load and demonstrates concomitant anti-inflammatory activity by reducing neutrophil numbers and markers of lung inflammation, such as bronchoalveolar lavage levels of tumor necrosis factor and myeloperoxidase. These findings show that an increased antimicrobial activity phenotype is provided by the elafin molecule and have implications for its use in S. aureus-associated local and systemic infections.

* Corresponding author. Mailing address: Rayne Laboratory, Respiratory Medicine Unit, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9AG, Scotland, United Kingdom. Phone: 44-1-31-650-6949. Fax: 44-1-31-650-4384. E-mail: J.Sallenave{at}ed.ac.uk.

Editor: J. N. Weiser

{dagger} J.W.M. and A.I.M. contributed equally to this study.

Infection and Immunity, June 2005, p. 3609-3617, Vol. 73, No. 6
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.6.3609-3617.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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