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

Aleksandr S. Lipatov, Samita Andreansky, Richard J. Webby, Diane J. Hulse, Jerold E. Rehg, Scott Krauss, Daniel R. Perez, Peter C. Doherty, Robert G. Webster, Mark Y. Sangster

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

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 IL1α, IL1β, IL6, IFN-γ 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.

Original languageEnglish (US)
Pages (from-to)1121-1130
Number of pages10
JournalJournal of General Virology
Volume86
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

ASJC Scopus subject areas

  • Virology

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