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

• Published in: Journal of general virology 2005-04, Vol.86 (4), p.1121-1130
• Main Authors: Lipatov, Aleksandr S, Andreansky, Samita, Webby, Richard J, Hulse, Diane J, Rehg, Jerold E, Krauss, Scott, Perez, Daniel R, Doherty, Peter C, Webster, Robert G, Sangster, Mark Y
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - immunology; Cytokines - biosynthesis; Disease Models, Animal; Female; Humans; Influenza A virus - genetics; Influenza A virus - pathogenicity; Influenza A Virus, H5N1 Subtype; Influenza virus; Influenza, Human - immunology; Influenza, Human - physiopathology; Influenza, Human - virology; Lung - immunology; Lung - physiopathology; Lung - virology; Mice; Mice, Inbred BALB C; Reassortant Viruses - genetics; Reassortant Viruses - pathogenicity; T-Lymphocytes - immunology; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - immunology; Virulence
• ISSN: 0022-1317; 1465-2099
• DOI: 10.1099/vir.0.80663-0

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 Glu 92 Asp 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