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Journal of Virology, March 2008, p. 2741-2751, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01712-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Avian Influenza Virus A/HK/483/97(H5N1) NS1 Protein Induces Apoptosis in Human Airway Epithelial Cells{triangledown}

W. Y. Lam,1 Julian W. Tang,1 Apple C. M. Yeung,1 Lawrence C. M. Chiu,2 Joseph J. Y. Sung,3 and Paul K. S. Chan1,3*

Departments of Microbiology,1 Biology,2 Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, New Territories, Hong Kong Special Administration Region, People's Republic of China3

Received 7 August 2007/ Accepted 26 December 2007

Avian H5N1 influenza virus causes a remarkably severe disease in humans, with an overall case fatality rate of greater than 50%. Human influenza A viruses induce apoptosis in infected cells, which can lead to organ dysfunction. To verify the role of H5N1-encoded NS1 in inducing apoptosis, the NS1 gene was cloned and expressed in human airway epithelial cells (NCI-H292 cells). The apoptotic events posttransfection were examined by a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end-labeling assay, flow cytometric measurement of propidium iodide, annexin V staining, and Western blot analyses with antibodies specific for proapoptotic and antiapoptotic proteins. We demonstrated that the expression of H5N1 NS1 protein in NCI-H292 cells was sufficient to induce apoptotic cell death. Western blot analyses also showed that there was prominent cleavage of poly(ADP-ribose) polymerase and activation of caspase-3, caspase-7, and caspase-8 during the NS1-induced apoptosis. The results of caspase inhibitor assays further confirmed the involvement of caspase-dependent pathways in the NS1-induced apoptosis. Interestingly, the ability of H5N1 NS1 protein to induce apoptosis was much enhanced in cells pretreated with Fas ligand (the time posttransfection required to reach >30% apoptosis was reduced from 24 to 6 h). Furthermore, 24 h posttransfection, an increase in Fas ligand mRNA expression of about 5.6-fold was detected in cells transfected with H5N1 NS1. In conclusion, we demonstrated that the NS1 protein encoded by avian influenza A virus H5N1 induced apoptosis in human lung epithelial cells, mainly via the caspase-dependent pathway, which encourages further investigation into the potential for the NS1 protein to be a novel therapeutic target.

* Corresponding author. Mailing address: Department of Microbiology, 1/F Clinical Science Building, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region, People's Republic of China. Phone: 852 2632 3333. Fax: 852 2647 3227. E-mail: paulkschan{at}cuhk.edu.hk

{triangledown} Published ahead of print on 16 January 2008.

Journal of Virology, March 2008, p. 2741-2751, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01712-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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