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Journal of Virology, October 2009, p. 10417-10426, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.00514-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice {triangledown} ,{dagger}

Adrianus C. M. Boon,1 Jennifer deBeauchamp,1 Anna Hollmann,1 Jennifer Luke,1 Malak Kotb,3 Sarah Rowe,3 David Finkelstein,2 Geoffrey Neale,2 Lu Lu,4 Robert W. Williams,4 and Richard J. Webby1*

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,1 Hartwell Center for Biotechnology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,2 VA Medical Center and MidSouth Center for Biodefense and Security, Memphis, Tennessee 38104,3 Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 381054

Received 12 March 2009/ Accepted 21 July 2009

Despite the prevalence of H5N1 influenza viruses in global avian populations, comparatively few cases have been diagnosed in humans. Although viral factors almost certainly play a role in limiting human infection and disease, host genetics most likely contribute substantially. To model host factors in the context of influenza virus infection, we determined the lethal dose of a highly pathogenic H5N1 virus (A/Hong Kong/213/03) in C57BL/6J and DBA/2J mice and identified genetic elements associated with survival after infection. The lethal dose in these hosts varied by 4 logs and was associated with differences in replication kinetics and increased production of proinflammatory cytokines CCL2 and tumor necrosis factor alpha in susceptible DBA/2J mice. Gene mapping with recombinant inbred BXD strains revealed five loci or Qivr (quantitative trait loci for influenza virus resistance) located on chromosomes 2, 7, 11, 15, and 17 associated with resistance to H5N1 virus. In conjunction with gene expression profiling, we identified a number of candidate susceptibility genes. One of the validated genes, the hemolytic complement gene, affected virus titer 7 days after infection. We conclude that H5N1 influenza virus-induced pathology is affected by a complex and multigenic host component.

* Corresponding author. Mailing address: St. Jude Children's Research Hospital, Department of Infectious Diseases, Mailstop 330, 262 Danny Thomas Place, Memphis, TN 38105. Phone: (901) 495-3014. Fax: (901) 523-2622. E-mail: Richard.Webby{at}stjude.org

{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. 10417-10426, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.00514-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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