Journal
JOURNAL OF GENERAL VIROLOGY
Volume 86, Issue -, Pages 1121-1130Publisher
SOC GENERAL MICROBIOLOGY
DOI: 10.1099/vir.0.80663-0
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Funding
- NCI NIH HHS [CA21760] Funding Source: Medline
- NIAID NIH HHS [AI29579, AI95357] Funding Source: Medline
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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 cytolkines; 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 3- 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 alpha, IL1 beta, IL6, IFN-gamma and chemokine KC, and decreased concentrations of the anti-inflammatory cytolkine 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.
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