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Journal of Virology, July 2005, p. 8802-8811, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8802-8811.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Influenza Virus Infection Increases p53 Activity: Role of p53 in Cell Death and Viral Replication

Elizabeth Turpin,{dagger},1 Kimberly Luke,{dagger},1 Jeremy Jones,1 Terrence Tumpey,2 Kouacou Konan,3 and Stacey Schultz-Cherry1*

Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706;,1 Influenza Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333;,2 Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 168023

Received 14 January 2005/ Accepted 28 March 2005

The induction of apoptotic cell death is a hallmark of influenza virus infection. Although a variety of cellular and viral proteins have been implicated in this process, to date no conserved cellular pathway has been identified. In this study, we report that the tumor suppressor protein p53 is essential for the induction of cell death in influenza virus-infected cells. In primary human lung cells, influenza virus increased p53 protein levels. This was also noted in the human lung cell line A549, along with the up-regulation of p53-dependent gene transcription. Reduction of p53 activity in A549 cells inhibited influenza virus-induced cell death as measured by trypan blue exclusion and caspase activity. These findings were not cell type specific. Influenza virus-induced cell death was absent in mouse embryo fibroblasts isolated from p53 knockout mice, which was not the case in wild-type mouse embryo fibroblasts, suggesting that p53 is a common cellular pathway leading to influenza virus-induced cell death. Surprisingly, inhibiting p53 activity led to elevated virus replication. Mechanistically, this may be due to the decrease in interferon signaling in p53-deficient cells, suggesting that functional p53 is involved in the interferon response to influenza infection. To our knowledge, these are the first studies demonstrating that p53 is involved in influenza virus-induced cell death and that inhibiting p53 leads to increased viral titers, potentially through modulation of the interferon response.

* Corresponding author. Mailing address: Department of Medical Microbiology and Immunology, 1300 University Avenue, Room 417 SMI, Madison, WI 53706. Phone: (608) 265-6462. Fax: (608) 262-8418. E-mail: slschul2{at}wisc.edu.

{dagger} E.T. and K.L. contributed equally to these studies and share first-authorship.

Journal of Virology, July 2005, p. 8802-8811, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8802-8811.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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