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Journal of Virology, April 2008, p. 3236-3249, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01887-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Fusion Protein of Respiratory Syncytial Virus Triggers p53-Dependent Apoptosis{triangledown}

Julia Eckardt-Michel,1 Markus Lorek,1 Diane Baxmann,1 Thomas Grunwald,2 Günther M. Keil,3 and Gert Zimmer1*

Institut für Virologie, Zentrum für Infektionsmedizin, Stiftung Tierärztliche Hochschule Hannover, Bünteweg 17, D-30559 Hannover, Germany,1 Abteilung für Mol. & Med. Virologie, Ruhr-Universität Bochum, Universitätsstrasse 150, D-44801 Bochum, Germany,2 Friedrich-Loeffler-Institut, Bundesforschungsinstitut für Tiergesundheit, Boddenblick 5a, D-17493 Greifswald-Insel Riems, Germany3

Received 29 August 2007/ Accepted 13 January 2008

Infection with respiratory syncytial virus (RSV) frequently causes inflammation and obstruction of the small airways, leading to severe pulmonary disease in infants. We show here that the RSV fusion (F) protein, an integral membrane protein of the viral envelope, is a strong elicitor of apoptosis. Inducible expression of F protein in polarized epithelial cells triggered caspase-dependent cell death, resulting in rigorous extrusion of apoptotic cells from the cell monolayer and transient loss of epithelial integrity. A monoclonal antibody directed against F protein inhibited apoptosis and was also effective if administered to A549 lung epithelial cells postinfection. F protein expression in epithelial cells caused phosphorylation of tumor suppressor p53 at serine 15, activation of p53 transcriptional activity, and conformational activation of proapoptotic Bax. Stable expression of dominant-negative p53 or p53 knockdown by RNA interference inhibited the apoptosis of RSV-infected A549 cells. HEp-2 tumor cells with low levels of p53 were not sensitive to RSV-triggered apoptosis. We propose a new model of RSV disease with the F protein as an initiator of epithelial cell shedding, airway obstruction, secondary necrosis, and consequent inflammation. This makes the RSV F protein a key target for the development of effective postinfection therapies.

* Corresponding author. Mailing address: Institut für Virologie, Zentrum für Infektionsmedizin, Stiftung Tierärztliche Hochschule Hannover, Bünteweg 17, D-30559 Hannover, Germany. Phone: 49 511 953 8460. Fax: 49 511 953 8898. E-mail: gert.zimmer{at}tiho-hannover.de

{triangledown} Published ahead of print on 23 January 2008.

Journal of Virology, April 2008, p. 3236-3249, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01887-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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