Quantifying the effects of mutations on receptor binding specificity of influenza viruses
Author(s)
Wei Hu
ABSTRACT
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.
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.
Cite this paper
nullHu, W. (2010) Quantifying the effects of mutations on receptor binding specificity of influenza viruses. Journal of Biomedical Science and Engineering, 3, 227-240. doi: 10.4236/jbise.2010.33031.
nullHu, W. (2010) Quantifying the effects of mutations on receptor binding specificity of influenza viruses. Journal of Biomedical Science and Engineering, 3, 227-240. doi: 10.4236/jbise.2010.33031.
References
[1] Webster, R.G. (1999) 1918 Spanish influenza: The secrets remain elusive. Proceedings of the National Academy of Sciences, USA, 96(4), 1164-1166. [2] Li, Q., Kash, J.C., Dugan, V.G., Wang, R.X., Jin, G.Z., Cunningham, R.E. and Taubenberger, J.K. (2009) Role of sialic acid binding specificity of the 1918 influenza virus hemagglutinin protein in virulence and pathogenesis for mice. Journal of Virology, 83(8), 3754-3761. [3] Matrosovich, M.N., Klenk, H. D. and Kawaoka, Y. (2006) Receptor specificity, host-range, and pathogenicity of influenza viruses. In Yoshihiro Kawaoka (ed.) Influenza Virology: Current Topics, Caister Academic Press, 95-137. [4] Zambon, M. (2007). Lessons from the 1918 influenza. Nature Biotech, 25, 433-434. [5] Gambaryan, A. Tuzikov, A., Pazynina, G., Bovin, N., Balish, A. and Klimov, A. (2006) Evolution of the receptor binding phenotype of influenza A (H5) viruses. Virology, 344(2), 432-438. [6] Yamada, S., Suzuki, Y., Suzuki, T., Le, M. Q., Nidom, C. A., Sakai-Tagawa, Y., Muramoto, Y., et al. (2006) Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature, 444(7117), 378-382. [7] Matrosovich, M., Tuzikov, A., Bovin, N., Gambaryan, A., and Klimov, A., et al. (2000) Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. Journal of Virology, 74(18), 8502-8512. [8] Bateman, A.C., Busch, M.G., Karasin, A.I., Bovin, N., and Olsen, C.W. (2008) Amino acid 226 in the hemagglutinin of H4N6 influenza virus determines binding affinity for alpha2, 6-linked sialic acid and infectivity levels in primary swine and human respiratory epithelial cells. Journal of Virology, 82(16), 8204-8209. [9] Wan, H., Sorrell, E.M., Song, H., Hossain, M.J., Ramirez-Nieto, G., et al. (2008) Replication and transmission of H9N2 influenza viruses in ferrets: Evaluation of pandemic potential. PLoS ONE, 3(8), e2923. [10] Rogers, G.N. and D’Souza, B.L. (1989) Receptor binding properties of human and animal H1 influenza virus isolates. Virology, 173, 317-322. [11] Matrosovich, M.N., Gambaryan, A.S., Teneberg, S., Piskarev, V.E., Yamnikova, S.S., et al. (1997) Avian influenza A viruses differ from human viruses by recognition of sialyloligosaccharides and gangliosides and by a higher conservation of the HA receptor-binding site. Virology, 233(1), 224-234. [12] Reid, A.H., Janczewski, T.A., Lourens, R.M., Elliot, A.J., Daniels, R.S., Berry, C.L., Oxford, J.S. and Taubenberger, J.K. (2003) 1918 influenza pandemic caused by highly conserved viruses with two receptor-binding variants. Emerg Infect Disease, 9(10), 1249-1253. [13] Shen, J., Ma, J. and Wang, Q. (2009) Evolutionary trends of A(H1N1) influenza virus hemagglutinin since 1918. PLoS ONE, 4(11), e7789. [14] Srinivasan, A., Viswanathan, K., Raman, R., Chandra- sekaran, A., Raguram, S., Tumpey, T.M., Sasisekharan, V. and Sasisekharan, R. (2008) Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses. Proceedings of the National Academy of Sciences, 105(8), 2800-2805. [15] Soundararajan, V., Tharakaraman, K., Raman, R., Raguram, S., Shriver, Z., Sasisekharan, V. and Sasisekharan R. (2009) Extrapolating from sequence–the 2009 H1N1 “swine” influenza virus. Nature Biotechnology, 27(6), 510-513. [16] Childs, R.A., Palma, A.S., Wharton, S., Matrosovich, T., Liu, Y., Chai, W.G., Campanero-Rhodes, M.A., Zhang, Y.B., Eickmann, M., Kiso, M., Hay, A., Matrosovich. M. and Feizi, T. (2009) Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nature Biotechnology, 27 (9), 797-799. [17] Hu, W. (2009) Analysis of correlated mutations, stalk motifs, and phylogenetic relationship of the 2009 influenza A virus neuraminidase sequences. Journal of Biomedical Science and Engineering, 2(7), 550-558. [18] Hu, W. (2010) The Interaction between the 2009 H1N1 influenza A hemagglutinin and neuraminidase: Mutations, co-mutations, and the NA stalk motifs. Journal of Biomedical Science and Engineering, 3, 1-12. [19] Veljkovic, V., Niman, H.L., Glisic, S., Veljkovic, N., Per- ovic, V. and Muller C.P. (2009). Identification of hemag- glutinin structural domain and polymorphisms which may modulate swine H1N1 interactions with human receptor. BMC Structural Biology, 9, 62. [20] Veljkovic, V., Veljkovic, N., Muller, C.P., Müller, S. Glisic, S., Perovic, V. and K?hler, H. (2009) Characteri- zation of conserved properties of hemagglutinin of H5N1 and human influenza viruses: Possible consequences for therapy and infection control. BMC Structural Biology, 7, 9-21. [21] Cosic, I. (1997) The resonant recognition model of macromolecular bioreactivity, theory and application. Berlin: Birkhauser Verlag. [22] Hu, W. (2010) Identification of highly conserved domains in hemagglutinin associated with the receptor binding specificity of influenza viruses: 2009 H1N1, avian H5N1, and swine. Journal of Biomedical Science and Engineering, 3, 114-123. [23] Katoh, K., Kuma, K., Toh, H. and Miyata, T. (2005) MAFFT version 5: Improvement in accuracy of multiple sequence alignment. Nucleic Acids Research, 33(2), 511- 518. [24] MacKay, D. (2003) Information theory, inference, and learning algorithms. Cambridge University Press. [25] KováccaronOVá, A., Ruttkay-Nedecky, G., Karol Haver- líK, I. and Janecccaronek, S. (2002) Sequence similarities and evolutionary relationships of influenza virus A hemagglutinins, Virus Genes, 24(1), 57-63. [26] Gamblin, S.J., Haire, L.F., Russell, R.J., Stevens, D.J., Xiao, B., Ha, Y., et al. (2004) The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science, 303, 1838-1842. [27] Daniels, R.S., Douglas, A.R., Skehel, J.J., Wiley, D.C., Naeve, C.W., Webster, R.G., Rogers, G.N. and Paulson, J. C. (1984). Antigenic analyses of influenza virus haemagglutinins with different receptorbinding specificities. Virology, 138, 174-177. [28] Srinivasan, A., Viswanathan, K., Raman, R., Chandrase- karan, A., Raguram, S., et al. (2008) Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses. Proceedings of the National Academy of Sciences, 105, 2800-2805. [29] Stevens, J., Blixt, O., Glaser, L., Taubenberger, J.K., Pal- ese, P., et al. (2006) Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. Journal of Molecular Biology, 355(5), 1143-1155. [30] Ayora-Talavera, G., Shelton, H., Scull, M.A., Ren, J., Jones, I.M., et al. (2009) Mutations in H5N1 influenza virus hemagglutinin that confer binding to human tracheal airway epithelium. PLoS ONE, 4(11), e7836. [31] Stevens, J., Blixt, O., Glaser, L., Taubenberger, J.K., Palese, P., et al. (2006) Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. Journal of Molecular Biology, 355(5), 1143-1155. [32] Stevens, J., Blixt, O., Chen, L.M., Donis, R.O., Paulson, J.C., et al. (2008) Recent avian H5N1 viruses exhibit increased propensity for acquiring human receptor specificity. Journal of Molecular Biology, 381(5), 1382- 1394. [33] Chandrasekaran, A., Srinivasan, A., Raman, R., Viswa- nathan, K., Raguram, S., Tumpey, T.M., Sasisekharan, V. and Sasisekharan, R. (1008) Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin. Nature Biotechnology, 26(1), 107-113.
[1] Webster, R.G. (1999) 1918 Spanish influenza: The secrets remain elusive. Proceedings of the National Academy of Sciences, USA, 96(4), 1164-1166. [2] Li, Q., Kash, J.C., Dugan, V.G., Wang, R.X., Jin, G.Z., Cunningham, R.E. and Taubenberger, J.K. (2009) Role of sialic acid binding specificity of the 1918 influenza virus hemagglutinin protein in virulence and pathogenesis for mice. Journal of Virology, 83(8), 3754-3761. [3] Matrosovich, M.N., Klenk, H. D. and Kawaoka, Y. (2006) Receptor specificity, host-range, and pathogenicity of influenza viruses. In Yoshihiro Kawaoka (ed.) Influenza Virology: Current Topics, Caister Academic Press, 95-137. [4] Zambon, M. (2007). Lessons from the 1918 influenza. Nature Biotech, 25, 433-434. [5] Gambaryan, A. Tuzikov, A., Pazynina, G., Bovin, N., Balish, A. and Klimov, A. (2006) Evolution of the receptor binding phenotype of influenza A (H5) viruses. Virology, 344(2), 432-438. [6] Yamada, S., Suzuki, Y., Suzuki, T., Le, M. Q., Nidom, C. A., Sakai-Tagawa, Y., Muramoto, Y., et al. (2006) Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature, 444(7117), 378-382. [7] Matrosovich, M., Tuzikov, A., Bovin, N., Gambaryan, A., and Klimov, A., et al. (2000) Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. Journal of Virology, 74(18), 8502-8512. [8] Bateman, A.C., Busch, M.G., Karasin, A.I., Bovin, N., and Olsen, C.W. (2008) Amino acid 226 in the hemagglutinin of H4N6 influenza virus determines binding affinity for alpha2, 6-linked sialic acid and infectivity levels in primary swine and human respiratory epithelial cells. Journal of Virology, 82(16), 8204-8209. [9] Wan, H., Sorrell, E.M., Song, H., Hossain, M.J., Ramirez-Nieto, G., et al. (2008) Replication and transmission of H9N2 influenza viruses in ferrets: Evaluation of pandemic potential. PLoS ONE, 3(8), e2923. [10] Rogers, G.N. and D’Souza, B.L. (1989) Receptor binding properties of human and animal H1 influenza virus isolates. Virology, 173, 317-322. [11] Matrosovich, M.N., Gambaryan, A.S., Teneberg, S., Piskarev, V.E., Yamnikova, S.S., et al. (1997) Avian influenza A viruses differ from human viruses by recognition of sialyloligosaccharides and gangliosides and by a higher conservation of the HA receptor-binding site. Virology, 233(1), 224-234. [12] Reid, A.H., Janczewski, T.A., Lourens, R.M., Elliot, A.J., Daniels, R.S., Berry, C.L., Oxford, J.S. and Taubenberger, J.K. (2003) 1918 influenza pandemic caused by highly conserved viruses with two receptor-binding variants. Emerg Infect Disease, 9(10), 1249-1253. [13] Shen, J., Ma, J. and Wang, Q. (2009) Evolutionary trends of A(H1N1) influenza virus hemagglutinin since 1918. PLoS ONE, 4(11), e7789. [14] Srinivasan, A., Viswanathan, K., Raman, R., Chandra- sekaran, A., Raguram, S., Tumpey, T.M., Sasisekharan, V. and Sasisekharan, R. (2008) Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses. Proceedings of the National Academy of Sciences, 105(8), 2800-2805. [15] Soundararajan, V., Tharakaraman, K., Raman, R., Raguram, S., Shriver, Z., Sasisekharan, V. and Sasisekharan R. (2009) Extrapolating from sequence–the 2009 H1N1 “swine” influenza virus. Nature Biotechnology, 27(6), 510-513. [16] Childs, R.A., Palma, A.S., Wharton, S., Matrosovich, T., Liu, Y., Chai, W.G., Campanero-Rhodes, M.A., Zhang, Y.B., Eickmann, M., Kiso, M., Hay, A., Matrosovich. M. and Feizi, T. (2009) Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nature Biotechnology, 27 (9), 797-799. [17] Hu, W. (2009) Analysis of correlated mutations, stalk motifs, and phylogenetic relationship of the 2009 influenza A virus neuraminidase sequences. Journal of Biomedical Science and Engineering, 2(7), 550-558. [18] Hu, W. (2010) The Interaction between the 2009 H1N1 influenza A hemagglutinin and neuraminidase: Mutations, co-mutations, and the NA stalk motifs. Journal of Biomedical Science and Engineering, 3, 1-12. [19] Veljkovic, V., Niman, H.L., Glisic, S., Veljkovic, N., Per- ovic, V. and Muller C.P. (2009). Identification of hemag- glutinin structural domain and polymorphisms which may modulate swine H1N1 interactions with human receptor. BMC Structural Biology, 9, 62. [20] Veljkovic, V., Veljkovic, N., Muller, C.P., Müller, S. Glisic, S., Perovic, V. and K?hler, H. (2009) Characteri- zation of conserved properties of hemagglutinin of H5N1 and human influenza viruses: Possible consequences for therapy and infection control. BMC Structural Biology, 7, 9-21. [21] Cosic, I. (1997) The resonant recognition model of macromolecular bioreactivity, theory and application. Berlin: Birkhauser Verlag. [22] Hu, W. (2010) Identification of highly conserved domains in hemagglutinin associated with the receptor binding specificity of influenza viruses: 2009 H1N1, avian H5N1, and swine. Journal of Biomedical Science and Engineering, 3, 114-123. [23] Katoh, K., Kuma, K., Toh, H. and Miyata, T. (2005) MAFFT version 5: Improvement in accuracy of multiple sequence alignment. Nucleic Acids Research, 33(2), 511- 518. [24] MacKay, D. (2003) Information theory, inference, and learning algorithms. Cambridge University Press. [25] KováccaronOVá, A., Ruttkay-Nedecky, G., Karol Haver- líK, I. and Janecccaronek, S. (2002) Sequence similarities and evolutionary relationships of influenza virus A hemagglutinins, Virus Genes, 24(1), 57-63. [26] Gamblin, S.J., Haire, L.F., Russell, R.J., Stevens, D.J., Xiao, B., Ha, Y., et al. (2004) The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science, 303, 1838-1842. [27] Daniels, R.S., Douglas, A.R., Skehel, J.J., Wiley, D.C., Naeve, C.W., Webster, R.G., Rogers, G.N. and Paulson, J. C. (1984). Antigenic analyses of influenza virus haemagglutinins with different receptorbinding specificities. Virology, 138, 174-177. [28] Srinivasan, A., Viswanathan, K., Raman, R., Chandrase- karan, A., Raguram, S., et al. (2008) Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses. Proceedings of the National Academy of Sciences, 105, 2800-2805. [29] Stevens, J., Blixt, O., Glaser, L., Taubenberger, J.K., Pal- ese, P., et al. (2006) Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. Journal of Molecular Biology, 355(5), 1143-1155. [30] Ayora-Talavera, G., Shelton, H., Scull, M.A., Ren, J., Jones, I.M., et al. (2009) Mutations in H5N1 influenza virus hemagglutinin that confer binding to human tracheal airway epithelium. PLoS ONE, 4(11), e7836. [31] Stevens, J., Blixt, O., Glaser, L., Taubenberger, J.K., Palese, P., et al. (2006) Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. Journal of Molecular Biology, 355(5), 1143-1155. [32] Stevens, J., Blixt, O., Chen, L.M., Donis, R.O., Paulson, J.C., et al. (2008) Recent avian H5N1 viruses exhibit increased propensity for acquiring human receptor specificity. Journal of Molecular Biology, 381(5), 1382- 1394. [33] Chandrasekaran, A., Srinivasan, A., Raman, R., Viswa- nathan, K., Raguram, S., Tumpey, T.M., Sasisekharan, V. and Sasisekharan, R. (1008) Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin. Nature Biotechnology, 26(1), 107-113.