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Journal of Virology, October 2009, p. 10557-10570, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.00330-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The NS1 Protein of the 1918 Pandemic Influenza Virus Blocks Host Interferon and Lipid Metabolism Pathways{triangledown} ,{dagger}

Rosalind Billharz,1 Hui Zeng,2 Sean C. Proll,1 Marcus J. Korth,1 Sharon Lederer,1 Randy Albrecht,3 Alan G. Goodman,1 Elizabeth Rosenzweig,1 Terrence M. Tumpey,2 Adolfo García-Sastre,3,4,5 and Michael G. Katze1*

Department of Microbiology and Washington National Primate Research Center, University of Washington, Seattle, Washington,1 Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia,2 Department of Microbiology,3 Department of Medicine, Division of Infectious Diseases,4 Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York5

Received 13 February 2009/ Accepted 11 July 2009

The "Spanish influenza" of 1918 claimed an unprecedented number of lives, yet the determinants of virulence for this virus are still not fully understood. Here, we used functional genomics and an in vitro human lung epithelial cell infection model to define the global host transcriptional response to the eight-gene 1918 virus. To better understand the role of the 1918 virus NS1 gene, we also evaluated the host response to a reassortant 1918 virus containing the NS1 gene from A/Texas/36/91 (a seasonal isolate of human influenza virus), as well as the host response to a reassortant of A/Texas/36/91 containing the 1918 NS1 gene. Genomic analyses revealed that the 1918 virus blocked the transcription of multiple interferon-stimulated genes and also downregulated a network of genes associated with lipid metabolism. In contrast, the expression of genes encoding chemokines and cytokines, which serve to attract infiltrating immune cells, was upregulated. Viruses containing the NS1 gene from A/Texas/36/91 induced a significant increase in type I interferon signaling but did not repress lipid metabolism. The 1918 NS1 gene may therefore have contributed to the virulence of the 1918 pandemic virus by disrupting the innate immune response, inducing hypercytokinemia, and by blocking the transcription of certain lipid-based proinflammatory mediators that function as part of the host antiviral response.

* Corresponding author. Mailing address: Department of Microbiology, University of Washington, Box 358070, Seattle, WA 98195-8070. Phone: (206) 732-6135. Fax: (206) 732-6056. E-mail: honey{at}u.washington.edu

{triangledown} Published ahead of print on 12 August 2009.

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

Journal of Virology, October 2009, p. 10557-10570, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.00330-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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