Abstract
ABSTRACTThe highly pathogenic avian influenza (HPAI) H5N1 viruses continue to circulate in nature and threaten public health. Although several viral determinants and host factors that influence the virulence of HPAI H5N1 viruses in mammals have been identified, the detailed molecular mechanism remains poorly defined and requires further clarification. In our previous studies, we characterized two naturally isolated HPAI H5N1 viruses that had similar viral genomes but differed substantially in their lethality in mice. In this study, we explored the molecular determinants and potential mechanism for this difference in virulence. By using reverse genetics, we found that a single amino acid at position 158 of the hemagglutinin (HA) protein substantially affected the systemic replication and pathogenicity of these H5N1 influenza viruses in mice. We further found that the G158N mutation introduced an N-linked glycosylation at positions 158 to 160 of the HA protein and that this N-linked glycosylation enhanced viral productivity in infected mammalian cells and induced stronger host immune and inflammatory responses to viral infection. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals.IMPORTANCE Highly pathogenic avian influenza (HPAI) H5N1 viruses continue to evolve in nature and threaten human health. Key mutations in the virus hemagglutinin (HA) protein or reassortment with other pandemic viruses endow HPAI H5N1 viruses with the potential for aerosol transmissibility in mammals. A thorough understanding of the pathogenic mechanisms of these viruses will help us to develop more effective control strategies; however, such mechanisms and virulent determinants for H5N1 influenza viruses have not been fully elucidated. In this study, we identified glycosylation at positions 158 to 160 of the HA protein of two naturally occurring H5N1 viruses as an important virulence determinant. This glycosylation event enhanced viral productivity, exacerbated the host response, and thereby contributed to the high pathogenicity of H5N1 virus in mice.
Highlights
The highly pathogenic avian influenza (HPAI) H5N1 viruses continue to circulate in nature and threaten public health
We examined the Madin-Darby canine kidney (MDCK) cells infected with Ca Mau/1180/2006 (CK/1180), chicken/Vietnam-Bac Lieu/1214/ 2007 (CK/1214), and CK/1180-1214HA at an multiplicity of infection (MOI) of 5 at 10 hpi by using ultrathin-section electron microscopy as described previously [38], and we found no difference in the morphology of the virions (Fig. 6B)
By using two HPAI H5N1 viruses (CK/1180 and CK/1214) with similar genomes but different pathogenicities in mice [31, 32], in this study, we demonstrated that a single amino acid mutation at position 158 of the HA protein had fundamental effect on the systemic replication and pathogenicity of these H5N1 influenza viruses in mice
Summary
The highly pathogenic avian influenza (HPAI) H5N1 viruses continue to circulate in nature and threaten public health. We further found that the G158N mutation introduced an N-linked glycosylation at positions 158 to 160 of the HA protein and that this N-linked glycosylation enhanced viral productivity in infected mammalian cells and induced stronger host immune and inflammatory responses to viral infection These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. We identified glycosylation at positions 158 to 160 of the HA protein of two naturally occurring H5N1 viruses as an important virulence determinant This glycosylation event enhanced viral productivity, exacerbated the host response, and thereby contributed to the high pathogenicity of H5N1 virus in mice. The amino acid at position 591 of PB2 is reported to be important for the efficient replication of pandemic H1N1 viruses in humans [22] and to substantially increase the pathogenicity of an avian H5N1 virus in mice [23]. We are acquiring important data in this area, the mechanism of host range and the virulent determinants of H5N1 influenza viruses have yet to be fully explored
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