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Infection and Immunity, September 2004, p. 4940-4947, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.4940-4947.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Streptococcus pneumoniae-Induced Caspase 6-Dependent Apoptosis in Lung Epithelium

Bernd Schmeck,1 Ralph Gross,1 Phillipe Dje N'Guessan,1 Andreas C. Hocke,1 Sven Hammerschmidt,2 Tim J. Mitchell,3 Simone Rosseau,1 Norbert Suttorp,1 and Stefan Hippenstiel1*

Department of Internal Medicine/Infectious Diseases, Charité-University Medicine Berlin, Berlin,1 Research Center for Infectious Diseases, University of Würzburg, Würzburg, Germany,2 Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom3

Received 16 January 2004/ Returned for modification 29 March 2004/ Accepted 1 June 2004

Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia and one of the most common causes of death due to infectious diseases in industrialized countries. Lung epithelium lines the airways and constitutes the first line of innate defense against respiratory pathogens. Little is known about the molecular interaction of pneumococci with lung epithelial cells. Apoptosis of lung epithelium is involved in some bacterial lung infections. In this study different pneumococcal strains specifically induced either apoptotic or necrotic death of human alveolar and bronchial epithelial cells. Pneumococcus-induced apoptosis did not depend on the virulence factors pneumolysin and H2O2. Apoptotic cells showed increased activity of caspases 6, 8, and 9 but not increased activity of caspase 3. Moreover, programmed cell death could be strongly reduced by a caspase 6 inhibitor and a pan-caspase inhibitor. Inhibitors of calpain and chymotrypsin- and trypsin-like proteases also reduced pneumococcus-induced apoptosis. Furthermore, pneumococcus-infected human alveolar epithelial cells showed Bid cleavage and reduced levels of Bcl2 and Bax. Overexpression of Bcl2 in these cells reduced apoptosis significantly. Thus, pneumococci induced apoptosis of human alveolar and bronchial epithelial cells. Programmed cell death was executed by caspase 6 and noncaspase proteases, but not by caspase 3, and could be blocked by overexpression of Bcl2.

* Corresponding author. Mailing address: Department of Internal Medicine/Infectious Diseases Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: 49 (30) 450 553052. Fax: 49 (30) 450 553906. E-mail: stefan.hippenstiel{at}charite.de.

Editor: S. H. E. Kaufmann

Infection and Immunity, September 2004, p. 4940-4947, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.4940-4947.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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