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pubmed:abstractText |
Humans infected by the highly pathogenic H5N1 avian influenza viruses (HPAIV) present unusually high concentrations in serum of proinflammatory cytokines and chemokines, which are believed to contribute to the high pathogenicity of these viruses. The hemagglutinins (HAs) of avian influenza viruses preferentially bind to sialic acids attached through ?2,3 linkages (SA?2,3) to the terminal galactose of carbohydrates on the host cell surface, while the HAs from human strains bind to ?2,6-linked SA (SA?2,6). To evaluate the role of the viral receptor specificity in promoting innate immune responses in humans, we generated recombinant influenza viruses, one bearing the HA and neuraminidase (NA) genes from the A/Vietnam/1203/2004 H5N1 HPAIV in an influenza A/Puerto Rico/8/1934 (A/PR/8/34) backbone with specificity for SA?2,3 and the other a mutant virus (with Q226L and G228S in the HA) with preferential receptor specificity for SA?2,6. Viruses with preferential affinity for SA?2,3 induced higher levels of proinflammatory cytokines and interferon (IFN)-inducible genes in primary human dendritic cells (DCs) than viruses with SA?2,6 binding specificity, and these differences were independent of viral replication, as shown by infections with UV-inactivated viruses. Moreover, human primary macrophages and respiratory epithelial cells showed higher expression of proinflammatory genes after infection with the virus with SA?2,3 affinity than after infection with the virus with SA?2,6 affinity. These data indicate that binding to SA?2,3 by H5N1 HPAIV may be sensed by human cells differently than binding to SA?2,6, inducing an exacerbated innate proinflammatory response in infected individuals.
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