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Journal of Virology, November 2008, p. 11294-11307, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.01192-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

H5N1 Avian Influenza Virus Induces Apoptotic Cell Death in Mammalian Airway Epithelial Cells {triangledown} ,{dagger}

Tomo Daidoji,1 Takaaki Koma,1,2,{ddagger} Anariwa Du,1,2 Cheng-Song Yang,1,2 Mayo Ueda,1,2 Kazuyoshi Ikuta,2 and Takaaki Nakaya1*

International Research Center for Infectious Diseases,1 Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan2

Received 8 June 2008/ Accepted 27 August 2008

In recent years, the highly pathogenic avian influenza virus H5N1 has raised serious worldwide concern about an influenza pandemic; however, the biology of H5N1 pathogenesis is largely unknown. To elucidate the mechanism of H5N1 pathogenesis, we prepared primary airway epithelial cells from alveolar tissues from 1-year-old pigs and measured the growth kinetics of three avian H5 influenza viruses (A/Crow/Kyoto/53/2004 [H5N1], A/Duck/Hong Kong/342/78 [H5N2], and A/Duck/Hong Kong/820/80 [H5N3]), the resultant cytopathicity, and possible associated mechanisms. H5N1, but not the other H5 viruses, strongly induced cell death in porcine alveolar epithelial cells (pAEpC), although all three viruses induced similar degrees of cytopathicity in chicken embryonic fibroblasts. Intracellular viral growth and the production of progeny viruses were comparable in pAEpC infected with each H5 virus. In contrast, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-positive cells were detected only in H5N1-infected pAEpC, and the activities of caspases 3, 8, and 9 were significantly elevated in pAEpC infected with H5N1, but not with H5N2 and H5N3. These results suggest that only H5N1 induces apoptosis in pAEpC. H5N1 cytopathicity was inhibited by adding the caspase inhibitor z-VAD-FMK; however, there were no significant differences in viral growth or release of progeny viruses. Further investigations using reverse genetics demonstrated that H5N1 hemagglutinin protein plays a critical role in inducing caspase-dependent apoptosis in infected pAEpC. H5N1-specific cytopathicity was also observed in human primary airway epithelial cells. Taken together, these data suggest that avian H5N1 influenza virus leads to substantial cell death in mammalian airway epithelial cells due to the induction of apoptosis.

* Corresponding author. Mailing address: International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka, 565-0871, Japan. Phone: 81-6-6879-4251. Fax: 81-6-6879-4252. E-mail: tnakaya{at}biken.osaka-u.ac.jp

{triangledown} Published ahead of print on 11 September 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: Institute for Animal Experimentation, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Journal of Virology, November 2008, p. 11294-11307, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.01192-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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