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Journal of Virology, November 2008, p. 11308-11317, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.00691-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Gene Expression Analysis of Host Innate Immune Responses during Lethal H5N1 Infection in Ferrets{triangledown} ,{dagger}

Cheryl M. Cameron,1,2,3 Mark J. Cameron,1,2,3 Jesus F. Bermejo-Martin,4 Longsi Ran,2 Luoling Xu,2 Patricia V. Turner,5 Ran Ran,2 Ali Danesh,1,2,3 Yuan Fang,1,2,3 Pak-Kei M. Chan,1,2,3 Nutan Mytle,6 Timothy J. Sullivan,7 Tassie L. Collins,7 Michael G. Johnson,7 Julio C. Medina,7 Thomas Rowe,1,2,3 and David J. Kelvin1,2,3*

Division of Immunology, International Institute of Infection and Immunity, Shantou University Medical College, Shantou, Guangdong, People's Republic of China,1 University Health Network, Toronto, Ontario, Canada,2 University of Toronto, Toronto, Ontario, Canada,3 Laboratorio de Immunologia de Mucosas, Universidad de Valladolid, Valladolid, Spain,4 Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada,5 Southern Research Institute, Birmingham, Alabama,6 Amgen, Inc., San Francisco, California7

Received 27 March 2008/ Accepted 21 July 2008

How viral and host factors contribute to the severe pathogenicity of the H5N1 subtype of avian influenza virus infection in humans is poorly understood. We identified three clusters of differentially expressed innate immune response genes in lungs from H5N1 (A/Vietnam/1203/04) influenza virus-infected ferrets by oligonucleotide microarray analysis. Interferon response genes were more strongly expressed in H5N1-infected ferret lungs than in lungs from ferrets infected with the less pathogenic H3N2 subtype. In particular, robust CXCL10 gene expression in H5N1-infected ferrets led us to test the pathogenic role of signaling via CXCL10's cognate receptor, CXCR3, during H5N1 influenza virus infection. Treatment of H5N1-infected ferrets with the drug AMG487, a CXCR3 antagonist, resulted in a reduction of symptom severity and delayed mortality compared to vehicle treatment. We contend that unregulated host interferon responses are at least partially responsible for the severity of H5N1 infection and provide evidence that attenuating the CXCR3 signaling pathway improves the clinical course of H5N1 infection in ferrets.

* Corresponding author. Mailing address: Division of Immunology, International Institute of Infection and Immunity, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong, P. R. China 515041. Phone: 86-754-8738699. Fax: 86-754-8544422. E-mail: dkelvin{at}uhnres.utoronto.ca

{triangledown} Published ahead of print on 6 August 2008.

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

Journal of Virology, November 2008, p. 11308-11317, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.00691-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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