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Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses

Samita Andreansky^2,

Daniel R. Perez^1,

Mark Y. Sangster^2,

¹ Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105–2794, USA
² Department of Immunology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105–2794, USA
³ Department of Pathology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105–2794, USA
⁴ Department of Pathology, University of Tennessee, Memphis, TN 38163, USA
⁵ Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia

Correspondence
Robert G. Webster
robert.webster{at}stjude.org

The severity of disease caused in humans by H5N1 influenza viruses remains unexplained. The NS gene of Hong Kong H5N1/97 viruses was shown to contribute to high pathogenicity of reassortants in a pig model. However, the molecular pathogenesis and host immune response underlying this phenomenon remain unclear. Here, in a mouse model, H1N1 A/Puerto Rico/8/34 (PR/8) reassortants that contained the H5N1/97 NS gene, the H5N1/01 NS gene, or an altered H5N1/97 NS gene encoding a Glu₉₂Asp substitution in NS1 was studied. The pathogenicity of reassortant viruses, the induction of cytokines and chemokine CXCL1 (KC) in the lungs and specific B- and T-cell responses was characterized. In mice infected with reassortant virus containing the H5N1/97 NS gene, the mouse lethal dose (50 %) and lung virus titres were similar to those of PR/8, which is highly pathogenic to mice. This reassortant virus required two more days than PR/8 to be cleared from the lungs of infected mice. Reassortants containing the altered H5N1/97 NS gene or the H5N1/01 NS gene demonstrated attenuated pathogenicity and lower lung titres in mice. Specific B- and T-cell responses were consistent with viral pathogenicity and did not explain the delayed clearance of the H5N1/97 NS reassortant. The reassortant induced elevated pulmonary concentrations of the inflammatory cytokines IL1, IL1, IL6, IFN- and chemokine KC, and decreased concentrations of the anti-inflammatory cytokine IL10. This cytokine imbalance is reminiscent of the clinical findings in two humans who died of H5N1/97 infection and may explain the unusual severity of the disease.

Present address: Department of Pediatrics, Steele Memorial Children's Research Center, University of Arizona, Tucson, AZ, USA.

Present address: Department of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742-3711, USA.

Present address: Department of Microbiology, The University of Tennessee, Walters Life Sciences F419, 1414 W. Cumberland Avenue, Knoxville, TN 37996, USA.

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