The hemagglutinin (HA) of influenza viruses facilitates receptor binding and membrane fusion, which is the initial step of virus infection. Human influenza viruses preferentially bind to receptors with α2-6 lin- kage...The hemagglutinin (HA) of influenza viruses facilitates receptor binding and membrane fusion, which is the initial step of virus infection. Human influenza viruses preferentially bind to receptors with α2-6 lin- kages to galactose (SAα2,6Gal), whereas avian influenza viruses prefer receptors with α2-3 linkages to galactose (SAα2,3Gal). The current 2009 H1N1 pandemic is caused by a novel influenza A virus that has its genetic materials from birds, humans, and pigs. Its pandemic nature is characterized clearly by its dual binding to the α2-3 as well as α2-6 receptors, because the seasonal human H1N1 virus only binds to the α2-6 receptor. In a previous study, the informational spectrum method (ISM), a bioinformatics technique, was applied to uncover one highly conserved region in the HA protein associated with receptor binding preference in each of various influenza subtypes. In the present study, we extended the previous work by discovering multiple such domains in HA of 2009 H1N1 and avian H5N1 to expand our repertoire of known key regions in HA responsible for receptor binding affinity. Three such domains in HA of 2009 H1N1 were found at residue positions 106 to 130, 150 to 174, and 191 to 221, and another three domains in HA of avian H5N1 were located at residue positions 46 to 65, 136 to 153, and 269 to 286. These identified domains could be utilized as therapeutic and diagnostic targets for the prevention and treatment of influenza infection.展开更多
The hemagglutinin (HA) of influenza viruses in itiates virus infection by binding receptors on host cells. Human influenza viruses preferenti ally bind to receptors with α2,6 linkages to gala ctose, avian viruses pre...The hemagglutinin (HA) of influenza viruses in itiates virus infection by binding receptors on host cells. Human influenza viruses preferenti ally bind to receptors with α2,6 linkages to gala ctose, avian viruses prefer receptors with α2,3 linkages to galactose, and swine viruses favor both types of receptors. The pandemic H1N1 2009 remains a global health concern in 2010. The novel 2009 H1N1 influenza virus has its ge netic components from avian, human, and sw ine viruses. Its pandemic nature is characterized clearly by its dual binding to the α2,3 as well as α2,6 receptors, because the seasonal human H1N1 virus only binds to the α2,6 receptor. In pr evious studies, the informational spectrum me thod (ISM), a bioinformatics method, was appli ed to uncover highly conserved regions in the HA protein associated with the primary receptor binding preference in various subtypes. In the present study, we extended the previous work by discovering multiple domains in HA associa ted with the secondary receptor binding prefer ence in various subtypes, thus characterizing the distinct dual binding nature of these viruses. The domains discovered in the HA proteins were mapped to the 3D homology model of HA, which could be utilized as therapeutic and diag nostic targets for the prevention and treatment of influenza infection.展开更多
Hemagglutinin (HA) of influenza viruses is a cylindrically shaped homotrimer, where each monomer comprises two disulfide-linked subdomains HA1 and HA2. Influenza infection is initiated by binding of HA1 to its host ce...Hemagglutinin (HA) of influenza viruses is a cylindrically shaped homotrimer, where each monomer comprises two disulfide-linked subdomains HA1 and HA2. Influenza infection is initiated by binding of HA1 to its host cell receptors and followed by the fusion between viral and host endosomal membranes mediated by HA2. Human influenza viruses preferentially bind to sialic acid that is linked to galactose by an α2,6-linkage (α2,6), whereas avian and swine influenza viruses preferentially recognize α2,3 or α 2,3/α2,6. For animal influenza viruses to cross host species barriers, their HA proteins must acquire mutations to gain the capacity to allow human-to-human transmission. In this study, the informational spectrum method (ISM), a bioinformatics approach, was applied to identify mutations and to elucidate the contribution to the receptor binding specificity from each mutation in HA1 in various subtypes within or between hosts, including 2009 human H1N1, avian H5N1, human H5N1, avian H1N1, and swine H1N2. Among others, our quantitative analysis indicated that the mutations in HA1 of 2009 human H1N1 collectively tended to reduce the swine binding affinity in the seasonal H1N1 strains and to increase that in the pandemic H1N1 strains. At the same time, they increased the human binding affinity in the pandemic H1N1 strains and had little impact on that in the seasonal H1N1 strains. The mutations between the consensus HA1 sequences of human H5N1 and avian H5N1 increased the avian binding affinity and decreased the human binding affinity in avian H5N1 while produced the opposite effects on those in human H5N1. Finally, the ISM was employed to analyze and verify several mutations in HA1 well known for their critical roles in binding specificity switch, including E190D/G225D in H1N1 and Q192R/ S223L/ Q226L/ G228S in H5N1.展开更多
文摘The hemagglutinin (HA) of influenza viruses facilitates receptor binding and membrane fusion, which is the initial step of virus infection. Human influenza viruses preferentially bind to receptors with α2-6 lin- kages to galactose (SAα2,6Gal), whereas avian influenza viruses prefer receptors with α2-3 linkages to galactose (SAα2,3Gal). The current 2009 H1N1 pandemic is caused by a novel influenza A virus that has its genetic materials from birds, humans, and pigs. Its pandemic nature is characterized clearly by its dual binding to the α2-3 as well as α2-6 receptors, because the seasonal human H1N1 virus only binds to the α2-6 receptor. In a previous study, the informational spectrum method (ISM), a bioinformatics technique, was applied to uncover one highly conserved region in the HA protein associated with receptor binding preference in each of various influenza subtypes. In the present study, we extended the previous work by discovering multiple such domains in HA of 2009 H1N1 and avian H5N1 to expand our repertoire of known key regions in HA responsible for receptor binding affinity. Three such domains in HA of 2009 H1N1 were found at residue positions 106 to 130, 150 to 174, and 191 to 221, and another three domains in HA of avian H5N1 were located at residue positions 46 to 65, 136 to 153, and 269 to 286. These identified domains could be utilized as therapeutic and diagnostic targets for the prevention and treatment of influenza infection.
文摘The hemagglutinin (HA) of influenza viruses in itiates virus infection by binding receptors on host cells. Human influenza viruses preferenti ally bind to receptors with α2,6 linkages to gala ctose, avian viruses prefer receptors with α2,3 linkages to galactose, and swine viruses favor both types of receptors. The pandemic H1N1 2009 remains a global health concern in 2010. The novel 2009 H1N1 influenza virus has its ge netic components from avian, human, and sw ine viruses. Its pandemic nature is characterized clearly by its dual binding to the α2,3 as well as α2,6 receptors, because the seasonal human H1N1 virus only binds to the α2,6 receptor. In pr evious studies, the informational spectrum me thod (ISM), a bioinformatics method, was appli ed to uncover highly conserved regions in the HA protein associated with the primary receptor binding preference in various subtypes. In the present study, we extended the previous work by discovering multiple domains in HA associa ted with the secondary receptor binding prefer ence in various subtypes, thus characterizing the distinct dual binding nature of these viruses. The domains discovered in the HA proteins were mapped to the 3D homology model of HA, which could be utilized as therapeutic and diag nostic targets for the prevention and treatment of influenza infection.
文摘Hemagglutinin (HA) of influenza viruses is a cylindrically shaped homotrimer, where each monomer comprises two disulfide-linked subdomains HA1 and HA2. Influenza infection is initiated by binding of HA1 to its host cell receptors and followed by the fusion between viral and host endosomal membranes mediated by HA2. Human influenza viruses preferentially bind to sialic acid that is linked to galactose by an α2,6-linkage (α2,6), whereas avian and swine influenza viruses preferentially recognize α2,3 or α 2,3/α2,6. For animal influenza viruses to cross host species barriers, their HA proteins must acquire mutations to gain the capacity to allow human-to-human transmission. In this study, the informational spectrum method (ISM), a bioinformatics approach, was applied to identify mutations and to elucidate the contribution to the receptor binding specificity from each mutation in HA1 in various subtypes within or between hosts, including 2009 human H1N1, avian H5N1, human H5N1, avian H1N1, and swine H1N2. Among others, our quantitative analysis indicated that the mutations in HA1 of 2009 human H1N1 collectively tended to reduce the swine binding affinity in the seasonal H1N1 strains and to increase that in the pandemic H1N1 strains. At the same time, they increased the human binding affinity in the pandemic H1N1 strains and had little impact on that in the seasonal H1N1 strains. The mutations between the consensus HA1 sequences of human H5N1 and avian H5N1 increased the avian binding affinity and decreased the human binding affinity in avian H5N1 while produced the opposite effects on those in human H5N1. Finally, the ISM was employed to analyze and verify several mutations in HA1 well known for their critical roles in binding specificity switch, including E190D/G225D in H1N1 and Q192R/ S223L/ Q226L/ G228S in H5N1.
