Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses.
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.
Lipatov
Aleksandr S
AS
Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
Andreansky
Samita
S
Department of Immunology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
Webby
Richard J
RJ
Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
Hulse
Diane J
DJ
Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
Rehg
Jerold E
JE
Department of Pathology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
Krauss
Scott
S
Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
Perez
Daniel R
DR
Department of Infectious Diseases (Division of Virology), St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
Doherty
Peter C
PC
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.
Webster
Robert G
RG
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.
Sangster
Mark Y
MY
Department of Immunology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA.
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
D016207:Cytokines; D017361:Viral Nonstructural Proteins