Molecular Features of Highly Pathogenic Avian and Human H5N1 Influenza A Viruses in Asia

Wei Hu

Department of Computer Science, Houghton College, Houghton, USA.

DOI: 10.4236/cmb.2012.22005                

Abstract

The highly pathogenic avian H5N1 influenza virus could infect humans with high mortality rate, even though it has not yet become efficiently transmissible among humans. This proteomic study investigated the molecular basis of interspecies transmission and host range of this lethal virus in Asia, due to its potential pandemic threat. Although there are host markers located in previous research between general avian and human influenza viruses, the novelty of our work was to uncover host markers between highly pathogenic avian and human H5N1 viruses in Asia. Many host markers we found were not present in the previous general markers, thus expanding the current repertoire of host markers with these strain-specific host markers. Ranked by their order of importance, the top 10 host markers discovered in this report were PB2_627, HA_325, NS1_205, PB2_524, HA_86, NA_201, NP_373, NS1_7, HA_156, NA_74, confirming our current knowledge that PB2_627 is the most critical site for distinguishing avian and human H5N1. We also identified several naturally-occurred mutations in the HA protein that might shift the receptor binding preference of Asian avian H5N1, since early detection of mutations that might lead to emergence of a new pandemic virus is of prime importance. Finally, we analyzed the distinctive interaction patterns within and between proteins of avian and human H5N1 in Asia at protein level and individual residue level. From multiple viewpoints, our findings reinforced the experimental observation that multiple genes of Asian avian H5N1 are involved in its gradual adaptation to human hosts.

Keywords

Entropy; H5N1; Hemagglutinin; Host Marker; Influenza; Informational Spectrum Method; Mutation; Mutual Information; Random Forest; Receptor Binding Specificity

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	K. Subbarao, A. Klimov, J. Katz, H. Regnery, W. Lim, H. Hall, M. Perdue, D. Swayne, C. Bender, J. Huang, M. Hemphill, T. Rowe, M. Shaw, X. Xu, K. Fukuda and N. Cox, “Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness,” Science, Vol. 279, No. 5349, 1998, pp. 393-396. doi:10.1126/science.279.5349.393
[2]	Y. Gao, et al., “Identification of Amino Acids in HA and PB2 Critical for the Transmission of H5N1 Avian Influenza Viruses in a Mammalian Host,” PLoS Pathogens, Vol. 5, No. 12, 2009, Article ID: 1000709. doi:10.1371/journal.ppat.1000709
[3]	J. Stevens, et al., “Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus,” Science, Vol. 312, No. 5772, 2006, pp. 404-410. doi:10.1126/science.1124513
[4]	P. Auewarakul, et al., “An Avian Influenza H5N1 Virus That Binds to a Human-Type Receptor,” Journal of Virology, Vol. 81, No. 18, 2007, pp. 9950-9955. doi:10.1128/JVI.00468-07
[5]	J. H. Beigel, et al., “Avian Influenza A (H5N1) Infection in Humans,” The New Journal of Medicine, Vol. 353, No. 13, 2005, pp. 1374-1385. doi:10.1056/NEJMra052211
[6]	O. Miotto, et al., “Identification of Human-to-Human Transmissibility Factors in PB2 Proteins of Influenza A by Large-Scale Mutual Information Analysis,” BMC Bioinformatics, Vol. 9, Suppl. 1, 2008, p. 18.
[7]	O. Miotto, et al., “Complete-Proteome Mapping of Human Influenza A Adaptive Mutations: Implications for Human Transmissibility of Zoonotic Strains,” PLoS One, Vol. 5, No. 2, 2010, p. 9025. doi:10.1371/journal.pone.0009025
[8]	D. King, Z. Miller, W. Jones and W. Hu, “Characteristic Sites in the Internal Proteins of Avian and Human Influenza Viruses,” Journal of Biomedical Science and Engineering, Vol. 3, No. 10, 2010, pp. 943-955. doi:10.4236/jbise.2010.310125
[9]	W. Hu, “Characterization of Asian and North American Avian H5N1,” American Journal of Molecular Biology, Vol. 1, No. 2, 2011, pp. 52-61. doi:10.4236/ajmb.2011.12007
[10]	W. Hu, “Novel Host Markers in the 2009 Pandemic H1N1 Influenza A Virus,” Journal of Biomedical Science and Engineering, Vol. 3, No. 6, 2010, pp. 584-601. doi:10.4236/jbise.2010.36081
[11]	W. Hu, “Nucleotide Host Markers in the Influenza A Viruses,” Journal of Biomedical Science and Engineering, Vol. 3, No. 7, 2010, pp. 684-699. doi:10.4236/jbise.2010.37093
[12]	T. D. Cline, et al., “Increased Pathogenicity of a Reassortant 2009 Pandemic H1N1 Influenza Virus Containing an H5N1 Hemagglutinin,” Journal of Virology, Vol. 85, No. 23, 2011, pp. 12262-12270. doi:10.1128/JVI.05582-11
[13]	Y. Kawaoka, “H5N1: Flu Transmission Work is Urgent,” Nature, Vol. 482, No. 7384, 2012, p. 155.
[14]	W. Hu, “Analysis of Correlated Mutations, Stalk Motifs, and Phylogenetic Relationship of the 2009 Influenza A Virus Neuraminidase Sequences,” Journal of Biomedical Science and Engineering, Vol. 2, No. 7, 2009, pp. 550-58. doi:10.4236/jbise.2009.27080
[15]	W. Hu, “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, Vol. 3, 2010, pp. 1-12. doi:10.4236/jbise.2010.31001
[16]	W. Hu, “Identification of Highly Conserved Domains in Hemagglutinin Associated with the Receptor Binding Specificity of Influenza Viruses: 2009 H1N1, Avian H5N1, and Swine H1N2,” Journal of Biomedical Science and Engineering, Vol. 3, 2010, pp. 114-123. doi:10.4236/jbise.2010.32017
[17]	W. Hu, “Quantifying the Effects of Mutations on Receptor Binding Specificity of Influenza Viruses,” Journal of Biomedical Science and Engineering, Vol. 3, 2010, pp. 227-240. doi:10.4236/jbise.2010.33031
[18]	W. Hu, “Subtle Differences in Receptor Binding Specificity and Gene Sequences of the 2009 Pandemic H1N1 Influenza Virus,” Advances in Bioscience and Biotechnology, Vol. 1, 2010, pp. 305-314. doi:10.4236/abb.2010.14040
[19]	W. Hu, “Correlated Mutations in the Four Influenza Proteins Essential for Viral RNA Synthesis, Host Adaptation, and Virulence: NP, PA, PB1, and PB2,” Natural Science, Vol. 2, No. 10, 2010, pp. 1138-1147. doi:10.4236/ns.2010.210141
[20]	W. Hu, “Highly Conserved Domains in Hemagglutinin of Influenza Viruses Characterizing Dual Receptor Binding,” Natural Science, Vol. 2, No. 9, 2010, pp. 1005-1014. doi:10.4236/ns.2009.29123
[21]	W. Hu, “Host Markers and Correlated Mutations in the Overlapping Genes of Influenza Viruses: M1, M2; NS1, NS2; and PB1, PB1-F2,” Natural Science, Vol. 2, No. 11, 2010, pp. 1225-1246. doi:10.4236/ns.2010.211150
[22]	W. Hu, “Receptor Binding Specificity and Origin of 2009 H1N1 Pandemic Influenza Virus,” Natural Science, Vol. 3, No. 3, 2011, pp. 234-248. doi:10.4236/ns.2011.33030
[23]	W. Hu, “New Mutational Trends in the HA Protein of 2009 H1N1 Pandemic Influenza Virus from May 2010 to February 2011,” Natural Science, Vol. 3, No. 5, 2011, pp. 379-387. doi:10.4236/ns.2011.35051
[24]	W. Hu, “Molecular Determinants for Receptor Specificity in Hemagglutinin Protein of 2009 Pandemic H1N1,” Proceedings of the 6th International Conference on Bioinformatics and Biomedical Engineering, Shanghai, 17-20 May 2012, pp. 629-632.
[25]	K. Katoh, K. Kuma, H. Toh and T. Miyata, “MAFFT Version 5: Improvement in Accuracy of Multiple Sequence Alignment,” Nucleic Acids Research, Vol. 33, No. 2, 2005, pp. 511-518. doi:10.1093/nar/gki198
[26]	I. Cosic, “The Resonant Recognition Model of Macromolecular Bioreactivity, Theory and Application,” Birkhauser Verlag, Berlin, 1997. doi:10.1007/978-3-0348-7475-5
[27]	V. Veljkovic, H. L. Niman, S. Glisic, N. Veljkovic, V. Perovic and C. P. Muller, “Identification of Hemagglutinin Structural Domain and Polymorphisms Which May Modulate Swine H1N1 Interactions with Human Receptor,” BMC Structural Biology, Vol. 9, 2009, p. 62. doi:10.1186/1472-6807-9-62
[28]	V. Veljkovic, N. Veljkovic, C. P. Muller, S. Müller, S. Glisic, V. Perovic and H. K?hler, “Characterization of Conserved Properties of Hemagglutinin of H5N1 and Human Influenza Viruses: Possible Consequences for Therapy and Infection Control,” BMC Structural Biology, Vol. 7, 2009, pp. 9-21.
[29]	T. A. Cover and J. A. Thomas, “Elements of Information Theory,” John Wiley and Sons, New York, 1991. doi:10.1002/0471200611
[30]	D. MacKay, “Information Theory, Inference, and Learning Algorithms,” Cambridge University Press, Cambridge, 2003.
[31]	M. Hatta, et al., “Growth of H5N1 Influenza A Viruses in the Upper Respiratory Tracts of Mice,” PLoS Pathogens, Vol. 3, No. 10, 2007, p. 133. doi:10.1371/journal.ppat.0030133
[32]	Y. Furuse, A. Suzuki, T. Kamigaki, H. Oshitani, “Evolution of the M Gene of the Influenza A Virus in Different Host Species: Large-Scale Sequence Analysis,” Virology Journal, Vol. 6, 2009, p. 67. doi:10.1186/1743-422X-6-67
[33]	N. V. Kaverin, et al., “Epitope mapping of the hemagglutinin molecule of a highly pathogenic H5N1 influenza virus by using monoclonal antibodies,” Virology Journal, Vol. 81, No. 23, 2007, pp. 12911-12917. doi:10.1128/JVI.01522-07
[34]	H. Wibawa, et al., “A Molecular and Antigenic Survey of H5N1 Highly Pathogenic Avian Influenza Virus Isolates from Smallholder Duck Farms in Central Java, Indonesia during 2007-2008,” Virology Journal, Vol. 8, 2011, p. 425. doi:10.1186/1743-422X-8-425
[35]	L. Breiman, “Random Forests,” Machine Learning, Vol. 45, No.1, 2001, pp. 5-32. doi:10.1023/A:1010933404324
[36]	R. Díaz-Uriarte and S. A. de Andrés, “Gene Selection and Classification of Microarray Data Using Random Forest,” BMC Bioinformatics, Vol. 7, 2006, p. 3. doi:10.1186/1471-2105-7-3
[37]	Y. G. Li, et al., “Characterization of H5N1 Influenza Viruses Isolated from Humans in Vitro,” Virology Journal, Vol. 7, 2010, p. 112. doi:10.1186/1743-422X-7-112
[38]	N. A. Ilyushina, et al., “Effect of Neuraminidase Inhibitor-Resistant Mutations on Pathogenicity of Clade 2.2 A/Turkey/15/06 (H5N1) Influenza Virus in Ferrets,” PLoS Pathogens, Vol. 6, No. 5, 2010, Article ID: 1000933. doi:10.1371/journal.ppat.1000933
[39]	G. Ayora-Talavera, et al., “Mutations in H5N1 Influenza Virus Hemagglutinin That Confer Binding to Human Tracheal Airway Epithelium,” PLoS One, Vol. 4, No. 11, 2009, p. 7836. doi:10.1371/journal.pone.0007836
[40]	A. Mehle and J. A. Doudna, “Adaptive Strategies of the Influenza Virus Polymerase for Replication in Humans,” Proceedings of the National Academy of Sciences, Vol. 106, No. 50, 2009, pp. 21312-21316. doi:10.1073/pnas.0911915106
[41]	G. J. Smith, et al., “Evolution and Adaptation of H5N1 Influenza Virus in Avian and Human Hosts in Indonesia and Vietnam,” Virology, Vol. 350, No. 2, 2006, pp. 258-268. doi:10.1016/j.virol.2006.03.048
[42]	B. J. Chen, et al., “The Influenza Virus M2 Protein Cytoplasmic Tail Interacts with the M1 Protein and Influences Virus Assembly at the Site of Virus Budding,” Journal of Virology, Vol. 82, No. 20, 2008, pp. 10059-10070. doi:10.1128/JVI.01184-08
[43]	A. C. Hurt, et al., “Susceptibility of Highly Pathogenic A (H5N1) Avian Influenza Viruses to the Neuraminidase Inhibitors and Adamantanes,” Antiviral Research, Vol. 73, 2007, pp. 228-231.
[44]	B. G. Hale, et al., “The Multifunctional NS1 Protein of Influenza A Viruses,” Journal of General Virology, Vol. 89, 2008, pp. 2359-2376. doi:10.1099/vir.0.2008/004606-0
[45]	H. Akarsu, K. Iwatsuki-Horimoto, T. Noda, E. Kawakami, H. Katsura, F. Baudin, T. Horimoto and Y. Kawaoka, “Structure-Based Design of NS2 Mutants for Attenuated Influenza A Virus Vaccines,” Virus Research, Vol. 155, No. 1, 2011, pp. 240-248. doi:10.1016/j.virusres.2010.10.014
[46]	K. Xu, et al., “Modification of Nonstructural Protein 1 of Influenza A Virus by Sumo1,” Journal of Virology, Vol. 85, No. 2, 2011, pp. 1086-1098. doi:10.1128/JVI.00877-10
[47]	Q. Zhu, et al., “A Naturally Occurring Deletion in Its NS Gene Contributes to the Attenuation of an H5N1 Swine Influenza Virus in Chickens,” Journal of Virology, Vol. 82, 2008, pp. 220-228. doi:10.1128/JVI.00978-07
[48]	A. S. Abdel-Moneim, et al., “Isolation and Characterization of Highly Pathogenic Avian Influenza Virus Subtype H5N1 from Donkeys,” Journal of Biomedical Science, Vol. 17, 2010, p. 25. doi:10.1186/1423-0127-17-25
[49]	Y. Ha, et al., “X-Ray Structures of H5 Avian and H9 Swine Influenza Virus Hemagglutinins Bound to Avian and Human Receptor Analogs,” Proceedings of the National Academy of Sciences, Vol. 98, 2001, pp. 11181-11186. doi:10.1073/pnas.201401198
[50]	R. Harvey, et al., “Restrictions to the Adaptation of Influenza a Virus H5 Hemagglutinin to the Human Host,” Journal of Virology, Vol. 78, 2004, pp. 502-507. doi:10.1128/JVI.78.1.502-507.2004
[51]	S. Yamada, et al., “Haemagglutinin Mutations Responsible for the Binding of H5N1 Influenza A Viruses to Human-Type Receptors,” Nature, Vol. 444, 2006, pp. 378-382. doi:10.1038/nature05264
[52]	W.-M. Jiang, et al., “Molecular Epidemiological Surveys of H5 subtype Highly Pathogenic Avian Influenza Viruses in Poultry in China during 2007-2009,” Journal of General Virology, Vol. 91, 2010, pp. 2491-2496.
[53]	C. I. Thompson, et al., “Infection of Human Airway Epithelium by Human and Avian Strains of Influenza A Virus,” Journal of Virology, Vol. 80, No. 16, 2006, pp. 8060-8068. doi:10.1128/JVI.00384-06