title: Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses.
abstract: 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 Glu92-->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 IL1alpha, IL1beta, IL6, IFN-gamma 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.
authors.affiliation: Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Aleksandr S
authors.initials: AS
authors.lastname: Lipatov
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Samita
authors.initials: S
authors.lastname: Andreansky
authors.affiliation: Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
authors.affiliation: Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Hulse
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.affiliation: Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Krauss
authors.affiliation: Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Perez
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia.|Department of Immunology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.affiliation: Department of Pathology, University of Tennessee, Memphis, TN 38163, USA.|Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Sangster
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype; D009980:Influenza A virus / Q000235:genetics / Q000472:pathogenicity*; D007251:Influenza, Human / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D008168:Lung / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D016865:Reassortant Viruses / Q000235:genetics / Q000472:pathogenicity*; D013601:T-Lymphocytes / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology*; D014774:Virulence
chemical_list: D016207:Cytokines; D017361:Viral Nonstructural Proteins