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Journal of Virology, August 2009, p. 8233-8246, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.02672-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Lack of Bax Prevents Influenza A Virus-Induced Apoptosis and Causes Diminished Viral Replication {triangledown}

Jeffrey E. McLean, Emmanuel Datan, Demetrius Matassov,{dagger} and Zahra F. Zakeri*

Department of Biology, Queens College and Graduate Center of the City University of New York, Flushing, New York 11367

Received 29 December 2008/ Accepted 18 May 2009

The ectopic overexpression of Bcl-2 restricts both influenza A virus-induced apoptosis and influenza A virus replication in MDCK cells, thus suggesting a role for Bcl-2 family members during infection. Here we report that influenza A virus cannot establish an apoptotic response without functional Bax, a downstream target of Bcl-2, and that both Bax and Bak are directly involved in influenza A virus replication and virus-induced cell death. Bak is substantially downregulated during influenza A virus infection in MDCK cells, and the knockout of Bak in mouse embryonic fibroblasts yields a dramatic rise in the rate of apoptotic death and a corresponding increase in levels of virus replication, suggesting that Bak suppresses both apoptosis and the replication of virus and that the virus suppresses Bak. Bax, however, is activated and translocates from the cytosol to the mitochondria; this activation is required for the efficient induction of apoptosis and virus replication. The knockout of Bax in mouse embryonic fibroblasts blocks the induction of apoptosis, restricts the infection-mediated activation of executioner caspases, and inhibits virus propagation. Bax knockout cells still die but by an alternative death pathway displaying characteristics of autophagy, similarly to our previous observation that influenza A virus infection in the presence of a pancaspase inhibitor leads to an increase in levels of autophagy. The knockout of Bax causes a retention of influenza A virus NP within the nucleus. We conclude that the cell and virus struggle to control apoptosis and autophagy, as appropriately timed apoptosis is important for the replication of influenza A virus.

* Corresponding author. Mailing address: Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367. Phone: (718) 997-3417. Fax: (718) 997-3429. E-mail: zahra_zakeri{at}hotmail.com

{triangledown} Published ahead of print on 3 June 2009.

{dagger} Present address: Division of Vaccine Vectors, Profectus BioSciences, Tarrytown, NY 10591.

Journal of Virology, August 2009, p. 8233-8246, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.02672-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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