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Journal of Virology, November 2009, p. 11102-11115, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00994-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Single-Amino-Acid Substitution in a Polymerase Protein of an H5N1 Influenza Virus Is Associated with Systemic Infection and Impaired T-Cell Activation in Mice ^,

Jamie L. Fornek,^1, Laura Gillim-Ross,^2,, Celia Santos,² Victoria Carter,¹ Jerrold M. Ward,³ Lily I. Cheng,³ Sean Proll,¹ Michael G. Katze,^1,* and Kanta Subbarao^2,

Department of Microbiology, University of Washington, Box 358070, Seattle, Washington 98195,¹ Laboratory of Infectious Diseases, NIAID, NIH, Bldg. 33, Room 3E13C_1, 33 North Dr., MSC 3203, Bethesda, Maryland 20892,² Comparative Medicine Branch, NIAID, NIH, Rockville, Maryland 20852³

Received 16 May 2009/ Accepted 7 August 2009

The transmission of H5N1 influenza viruses from birds to humans poses a significant public health threat. A substitution of glutamic acid for lysine at position 627 of the PB2 protein of H5N1 viruses has been identified as a virulence determinant. We utilized the BALB/c mouse model of H5N1 infection to examine how this substitution affects virus-host interactions and leads to systemic infection. Mice infected with H5N1 viruses containing lysine at amino acid 627 in the PB2 protein exhibited an increased severity of lesions in the lung parenchyma and the spleen, increased apoptosis in the lungs, and a decrease in oxygen saturation. Gene expression profiling revealed that T-cell receptor activation was impaired at 2 days postinfection (dpi) in the lungs of mice infected with these viruses. The inflammatory response was highly activated in the lungs of mice infected with these viruses and was sustained at 4 dpi. In the spleen, immune-related processes including NK cell cytotoxicity and antigen presentation were highly activated by 2 dpi. These differences are not attributable solely to differences in viral replication in the lungs but to an inefficient immune response early in infection as well. The timing and magnitude of the immune response to highly pathogenic influenza viruses is critical in determining the outcome of infection. The disruption of these factors by a single-amino-acid substitution in a polymerase protein of an influenza virus is associated with severe disease and correlates with the spread of the virus to extrapulmonary sites.

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* Corresponding author. Mailing address: Department of Microbiology, University of Washington, Box 358070, Seattle, WA 98195. Phone: (206) 732-6136. Fax: (206) 732-6055. E-mail: honey{at}u.washington.edu

Published ahead of print on 19 August 2009.

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

These authors contributed equally to this work.

Present address: Colorado Department of Public Health and Environment, 8100 Lowry Blvd., Denver, CO 80230.

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Journal of Virology, November 2009, p. 11102-11115, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00994-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.