The interaction between the 2009 H1N1 influenza A hemagglutinin and neuraminidase: mutations, co-mutations, and the NA stalk motifs
Author(s)
Wei Hu*
ABSTRACT
As the world is closely watching the current 2009 H1N1 pandemic unfold, there is a great interest and need in understanding its origin, genetic structures, virulence, and pathogenicity. The two surface proteins, hemagglutinin (HA) and neuraminidase (NA), of the influenza virus have been the focus of most flu research due to their crucial biological functions. In our previous study on 2009 H1N1, three aspects of NA were investigated: the mutations and co-mutations, the stalk motifs, and the phylogenetic analysis. In this study, we turned our attention to HA and the interaction between HA and NA. The 118 mutations of 2009 H1N1 HA were found and mapped to the 3D homology model of H1, and the mutations on the five epitope regions on H1 were identified. This information is essential for developing new drugs and vaccine. The distinct response patterns of HA to the changes of NA stalk motifs were discovered, illustrating the functional dependence between HA and NA. With help from our previous results, two co-mutation networks were uncovered, one in HA and one in NA, where each mutation in one network co-mutates with the mutations in the other network across the two proteins HA and NA. These two networks residing in HA and NA separately may provide a functional linkage between the mutations that can impact the drug binding sites in NA and those that can affect the host immune response or vaccine efficacy in HA. Our findings demonstrated the value of conducting timely analysis on the 2009 H1N1 virus and of the integrated approach to studying both surface proteins HA and NA together to reveal their interdependence, which could not be accomplished by studying them individually.
As the world is closely watching the current 2009 H1N1 pandemic unfold, there is a great interest and need in understanding its origin, genetic structures, virulence, and pathogenicity. The two surface proteins, hemagglutinin (HA) and neuraminidase (NA), of the influenza virus have been the focus of most flu research due to their crucial biological functions. In our previous study on 2009 H1N1, three aspects of NA were investigated: the mutations and co-mutations, the stalk motifs, and the phylogenetic analysis. In this study, we turned our attention to HA and the interaction between HA and NA. The 118 mutations of 2009 H1N1 HA were found and mapped to the 3D homology model of H1, and the mutations on the five epitope regions on H1 were identified. This information is essential for developing new drugs and vaccine. The distinct response patterns of HA to the changes of NA stalk motifs were discovered, illustrating the functional dependence between HA and NA. With help from our previous results, two co-mutation networks were uncovered, one in HA and one in NA, where each mutation in one network co-mutates with the mutations in the other network across the two proteins HA and NA. These two networks residing in HA and NA separately may provide a functional linkage between the mutations that can impact the drug binding sites in NA and those that can affect the host immune response or vaccine efficacy in HA. Our findings demonstrated the value of conducting timely analysis on the 2009 H1N1 virus and of the integrated approach to studying both surface proteins HA and NA together to reveal their interdependence, which could not be accomplished by studying them individually.
Cite this paper
nullHu, 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. doi: 10.4236/jbise.2010.31001.
nullHu, 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. doi: 10.4236/jbise.2010.31001.
References
[1] Castrucci, M.R. and Kawaoka, Y. (1993) Biologic importance of neuraminidase stalk length in influenza A virus. J Virol, 67, 759-764. [2] Els, M.C., Air, G.M., Murti, K.G. et al. (1985) An 18-amino acid deletion in an influenza neuraminidase. Virology, 142, 241-247. [3] Zhou, H.B., Yu, Z.J., Hu, Y. Tu, J.G. et al. (2009) The special neuraminidase stalk-motif responsible for increased virulence and pathogenesis of H5N1 influenza A virus. PLoS One, 4(7), 6277. [4] Wagner, R., Matrosovich, M. and Klenk, H.D. (2002) Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev. Med. Virol, 12, 159-166. [5] Lu, B., Zhou, H.L., Ye, D., Kemble, G. and Jin, H. (2005) Improvement of influenza A/Fujian/411/02 (H3N2) virus growth in embryonated chicken eggs by balancing the hemagglutinin and neuraminidase activities, using reverse genetics. Journal of Virology, 79, 6763-6771. [6] 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, 550-555 [7] Sebastian, M.S., Ma, J.M., Raphael, T.C.L., Fernanda, L. S. and Frank, E. (2009) Mapping the sequence mutations of the 2009 H1N1 influenza A virus neuraminidase relative to drug and antibody binding sites. Biol Direct, 4(18). [8] Laurel, G., James, S., Dmitriy Z. et al. (2005) A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. Journal of Virology, 79, 11533-11536. [9] Skehel, J.J., Stevens, D.J., Daniels, R.S., Douglas, A.R., Knossow, M. et al. (1984) A carbohydrate side chain on hemagglutinins of Hong Kong influenza viruses inhibits recognition by a monoclonal antibody. Proc Natl Acad Sci U S A, 81, 1779-1783. [10] Wiley, D.C., Wilson, I.A. and Skehel, J.J. (1981) Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature, 289, 373-378. [11] Caton, A.J., Brownlee, G.G., Yewdell, J.W. and Gerhard, W. (1982) The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell, 31, 417-27. [12] Tsuchiya, E., Sugawara, K., Hongo, S., Matsuzaki, Y., Muraki, Y. et al. (2001) Antigenic structure of the haemagglutinin of human influenza A/H2N2 virus. J Gen Virol, 82, 2475-2484. [13] Michael, W.D. and Pan, K.Y. (2009) The epitope regions of H1-subtype influenza A, with application to vaccine efficacy. Protein Engineering, Design & Selection, 22, 543-546. [14] Katoh, K., Kuma, K., Toh, H., Miyata, T. (2005) MAFFT version 5: improvement in accuracy of multiple sequence alignment. Nucleic Acids Res, 33, 511-518. [15] David, M. (2003) Information theory, inference, and learning algorithms. Cambridge University Press. Breiman, L. (2001) Random forests, machine learning, 45 (1), 5-32. [16] Cox, T.F. and Cox, M.A.A. (2001), Multidimensional scaling, chapman and hall. [17] Colman, P.M., Hoyne, P.A. and Lawrence, M.C. (1993) Sequence and structure alignment of paramyxovirus hemagglutinin-neuraminidase with influenza virus neuraminidase. J. Virol, 67, 2972-2980. [18] Andrea, K., Gabriel, R.N. and Ivan, K.H., Sccarontefan, J. (2002) Sequence similarities and evolutionary relationships of influenza virus A hemagglutinins, Virus Genes, 24, 57-63. [19] Waterhouse, A.M., Procter, J.B., Martin, D.M.A., Clamp, M and Barton, G.J. (2009) Jalview version 2 – A multiple sequence alignment editor and analysis workbench. Bioinformatics, 5, 1189-1191. [20] Enrique, T. and Mu?noz, M.W.D. (2005) Epitope analysis for influenza vaccine design. Vaccine, 23, 1144-1148. [21] Weis, W., Brown, J.H., Cusack, S., Paulson, J.C., Skehel, J.J. and Wiley, D.C. (1988) Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature, 333(6172), 426-31. [22] Veljko, V., Henry, L.N., Sanja G. et al. (2009) Identification of hemagglutinin structural domain and polymorphisms which may modulate swine H1N1 interactions with human receptor. BMC Structural Biology, 9(62). [23] Nikolai, V.K., Mikhail, N.M. and Aleksandra, S.G. (2000) Intergenic HA–NA interactions in influenza A virus: postreassortment substitutions of charged amino acid in the hemagglutinin of different subtypes. Virus Research, 66,123-129. [24] Garten, R.J., Davis, C.T., Russell, C.A. et al. (2009) Antigenic and genetic characteristics of swine-origin 2009 A (H1N1) influenza viruses circulating in humans. Science, 325, 197-201. [25] Kumar, S., Nei, M., Dudley, J. and Tamura. K., (2008) MEGA: a biologist-centric software for evolutionary analysis of DNA and protein sequences. Brief Bioinformatics, 9, 299-306. [26] Lu, B., Zhou, H., Ye, D., Kemble, G. and Jin, H., (2005) Improvement of influenza A/Fujian/411/02 (H3N2) virus growth in embryonated chicken eggs by balancing the hemagglutinin and neuraminidase activities, using reverse genetics. J. Virol, 79, 6763-6771. [27] Jin, H., Zhou, H., Liu, H., Chan, W.N., Adhikary, L. et al. (2005) Two residues in the hemagglutinin of A/Fujian/ 411/02-like influenza viruses are responsible for antigenic drift from A/Panama/2007/99. Virology, 336, 113- 119. [28] Elodie G., Naomi A.S., Martin S. et al. (2005) Large- scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. Nature, 437, 1162-1166. [29] Du, X.J., Wang, Z., Wu, A.P., Song, L., Cao, Y., Hang, H.Y. and Jiang, T.J. (2008) Networks of genomic co-occurrence capture characteristics of human influenza A (H3N2) evolution. Genome Res, 18, 178-187. [30] Huang, J.W., King, C.C. and Yang, J.M. (2009) Co-evolution positions and rules for antigenic variants of human influenza A/H3N2 viruses. BMC Bioinformatics, 10(Suppl 1), S41. [31] Michel, W., Chen, C.C., Kemp, M.M. and Linhard, R.J. (2009) Synthesis and biological evaluation of non- hydrolyzable 1,2,3-triazole-linked sialic acid derivatives as neuraminidase inhibitors. European Journal of Organic Chemistry, 2009(16), 2587. [32] Gocn?′k, M., Fislova′, T., Mucha, V., Sla′dkova′, T. et al. (2008) Antibodies induced by the HA2 glycopolypeptide of influenza virus haemagglutinin improve recovery from influenza A virus infection. Journal of General Virology, 89, 958-967.
[1] Castrucci, M.R. and Kawaoka, Y. (1993) Biologic importance of neuraminidase stalk length in influenza A virus. J Virol, 67, 759-764. [2] Els, M.C., Air, G.M., Murti, K.G. et al. (1985) An 18-amino acid deletion in an influenza neuraminidase. Virology, 142, 241-247. [3] Zhou, H.B., Yu, Z.J., Hu, Y. Tu, J.G. et al. (2009) The special neuraminidase stalk-motif responsible for increased virulence and pathogenesis of H5N1 influenza A virus. PLoS One, 4(7), 6277. [4] Wagner, R., Matrosovich, M. and Klenk, H.D. (2002) Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev. Med. Virol, 12, 159-166. [5] Lu, B., Zhou, H.L., Ye, D., Kemble, G. and Jin, H. (2005) Improvement of influenza A/Fujian/411/02 (H3N2) virus growth in embryonated chicken eggs by balancing the hemagglutinin and neuraminidase activities, using reverse genetics. Journal of Virology, 79, 6763-6771. [6] 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, 550-555 [7] Sebastian, M.S., Ma, J.M., Raphael, T.C.L., Fernanda, L. S. and Frank, E. (2009) Mapping the sequence mutations of the 2009 H1N1 influenza A virus neuraminidase relative to drug and antibody binding sites. Biol Direct, 4(18). [8] Laurel, G., James, S., Dmitriy Z. et al. (2005) A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. Journal of Virology, 79, 11533-11536. [9] Skehel, J.J., Stevens, D.J., Daniels, R.S., Douglas, A.R., Knossow, M. et al. (1984) A carbohydrate side chain on hemagglutinins of Hong Kong influenza viruses inhibits recognition by a monoclonal antibody. Proc Natl Acad Sci U S A, 81, 1779-1783. [10] Wiley, D.C., Wilson, I.A. and Skehel, J.J. (1981) Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature, 289, 373-378. [11] Caton, A.J., Brownlee, G.G., Yewdell, J.W. and Gerhard, W. (1982) The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell, 31, 417-27. [12] Tsuchiya, E., Sugawara, K., Hongo, S., Matsuzaki, Y., Muraki, Y. et al. (2001) Antigenic structure of the haemagglutinin of human influenza A/H2N2 virus. J Gen Virol, 82, 2475-2484. [13] Michael, W.D. and Pan, K.Y. (2009) The epitope regions of H1-subtype influenza A, with application to vaccine efficacy. Protein Engineering, Design & Selection, 22, 543-546. [14] Katoh, K., Kuma, K., Toh, H., Miyata, T. (2005) MAFFT version 5: improvement in accuracy of multiple sequence alignment. Nucleic Acids Res, 33, 511-518. [15] David, M. (2003) Information theory, inference, and learning algorithms. Cambridge University Press. Breiman, L. (2001) Random forests, machine learning, 45 (1), 5-32. [16] Cox, T.F. and Cox, M.A.A. (2001), Multidimensional scaling, chapman and hall. [17] Colman, P.M., Hoyne, P.A. and Lawrence, M.C. (1993) Sequence and structure alignment of paramyxovirus hemagglutinin-neuraminidase with influenza virus neuraminidase. J. Virol, 67, 2972-2980. [18] Andrea, K., Gabriel, R.N. and Ivan, K.H., Sccarontefan, J. (2002) Sequence similarities and evolutionary relationships of influenza virus A hemagglutinins, Virus Genes, 24, 57-63. [19] Waterhouse, A.M., Procter, J.B., Martin, D.M.A., Clamp, M and Barton, G.J. (2009) Jalview version 2 – A multiple sequence alignment editor and analysis workbench. Bioinformatics, 5, 1189-1191. [20] Enrique, T. and Mu?noz, M.W.D. (2005) Epitope analysis for influenza vaccine design. Vaccine, 23, 1144-1148. [21] Weis, W., Brown, J.H., Cusack, S., Paulson, J.C., Skehel, J.J. and Wiley, D.C. (1988) Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature, 333(6172), 426-31. [22] Veljko, V., Henry, L.N., Sanja G. et al. (2009) Identification of hemagglutinin structural domain and polymorphisms which may modulate swine H1N1 interactions with human receptor. BMC Structural Biology, 9(62). [23] Nikolai, V.K., Mikhail, N.M. and Aleksandra, S.G. (2000) Intergenic HA–NA interactions in influenza A virus: postreassortment substitutions of charged amino acid in the hemagglutinin of different subtypes. Virus Research, 66,123-129. [24] Garten, R.J., Davis, C.T., Russell, C.A. et al. (2009) Antigenic and genetic characteristics of swine-origin 2009 A (H1N1) influenza viruses circulating in humans. Science, 325, 197-201. [25] Kumar, S., Nei, M., Dudley, J. and Tamura. K., (2008) MEGA: a biologist-centric software for evolutionary analysis of DNA and protein sequences. Brief Bioinformatics, 9, 299-306. [26] Lu, B., Zhou, H., Ye, D., Kemble, G. and Jin, H., (2005) Improvement of influenza A/Fujian/411/02 (H3N2) virus growth in embryonated chicken eggs by balancing the hemagglutinin and neuraminidase activities, using reverse genetics. J. Virol, 79, 6763-6771. [27] Jin, H., Zhou, H., Liu, H., Chan, W.N., Adhikary, L. et al. (2005) Two residues in the hemagglutinin of A/Fujian/ 411/02-like influenza viruses are responsible for antigenic drift from A/Panama/2007/99. Virology, 336, 113- 119. [28] Elodie G., Naomi A.S., Martin S. et al. (2005) Large- scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. Nature, 437, 1162-1166. [29] Du, X.J., Wang, Z., Wu, A.P., Song, L., Cao, Y., Hang, H.Y. and Jiang, T.J. (2008) Networks of genomic co-occurrence capture characteristics of human influenza A (H3N2) evolution. Genome Res, 18, 178-187. [30] Huang, J.W., King, C.C. and Yang, J.M. (2009) Co-evolution positions and rules for antigenic variants of human influenza A/H3N2 viruses. BMC Bioinformatics, 10(Suppl 1), S41. [31] Michel, W., Chen, C.C., Kemp, M.M. and Linhard, R.J. (2009) Synthesis and biological evaluation of non- hydrolyzable 1,2,3-triazole-linked sialic acid derivatives as neuraminidase inhibitors. European Journal of Organic Chemistry, 2009(16), 2587. [32] Gocn?′k, M., Fislova′, T., Mucha, V., Sla′dkova′, T. et al. (2008) Antibodies induced by the HA2 glycopolypeptide of influenza virus haemagglutinin improve recovery from influenza A virus infection. Journal of General Virology, 89, 958-967.