Quantifying within-host diversity of H5N1 influenza viruses in humans and poultry in Cambodia

Autoři: Louise H. Moncla aff001;  Trevor Bedford aff001;  Philippe Dussart aff003;  Srey Viseth Horm aff003;  Sareth Rith aff003;  Philippe Buchy aff004;  Erik A. Karlsson aff003;  Lifeng Li aff005;  Yongmei Liu aff005;  Huachen Zhu aff005;  Yi Guan aff005;  Thomas C. Friedrich aff007;  Paul F. Horwood aff003
Působiště autorů: Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America aff001;  University of Washington, Seattle, Washington, United States of America aff002;  Virology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh, Cambodia aff003;  GlaxoSmithKline, Vaccines R&D, Singapore, Singapore aff004;  Joint Influenza Research Centre (SUMC/HKU), Shantou University Medical College, Shantou, People's Republic of China aff005;  State Key Laboratory of Emerging Infectious Diseases/Centre of Influenza Research, School of Public Health, The University of Hong Kong, Hong Kong, SAR, People's Republic of China aff006;  Department of Pathobiological Sciences, University of Wisconsin School of Veterinary Medicine, Madison, WI, United States of America aff007;  Wisconsin National Primate Research Center, Madison, WI, United States of America aff008;  College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Australia aff009
Vyšlo v časopise: Quantifying within-host diversity of H5N1 influenza viruses in humans and poultry in Cambodia. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008191
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008191


Avian influenza viruses (AIVs) periodically cross species barriers and infect humans. The likelihood that an AIV will evolve mammalian transmissibility depends on acquiring and selecting mutations during spillover, but data from natural infection is limited. We analyze deep sequencing data from infected humans and domestic ducks in Cambodia to examine how H5N1 viruses evolve during spillover. Overall, viral populations in both species are predominated by low-frequency (<10%) variation shaped by purifying selection and genetic drift, and half of the variants detected within-host are never detected on the H5N1 virus phylogeny. However, we do detect a subset of mutations linked to human receptor binding and replication (PB2 E627K, HA A150V, and HA Q238L) that arose in multiple, independent humans. PB2 E627K and HA A150V were also enriched along phylogenetic branches leading to human infections, suggesting that they are likely human-adaptive. Our data show that H5N1 viruses generate putative human-adapting mutations during natural spillover infection, many of which are detected at >5% frequency within-host. However, short infection times, genetic drift, and purifying selection likely restrict their ability to evolve extensively during a single infection. Applying evolutionary methods to sequence data, we reveal a detailed view of H5N1 virus adaptive potential, and develop a foundation for studying host-adaptation in other zoonotic viruses.

Klíčová slova:

Animal phylogenetics – Cell binding – Ducks – H5N1 – Microbial mutation – Mutation detection – Respiratory infections – Viral replication


1. Organization WH. Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003–2018.

2. Chen H, Smith GJD, Li KS, Wang J, Fan XH, Rayner JM, et al. Establishment of multiple sublineages of H5N1 influenza virus in Asia: Implications for pandemic control. Proceedings of the National Academy of Sciences. 2006; doi: 10.1073/pnas.0511120103 16473931

3. Nguyen DT, Jang Y, Nguyen TD, Jones J, Shepard SS, Yang H, et al. Shifting Clade Distribution, Reassortment, and Emergence of New Subtypes of Highly Pathogenic Avian Influenza A(H5) Viruses Collected from Vietnamese Poultry from 2012 to 2015. J Virol. 2017; doi: 10.1128/JVI.01708-16 28003481

4. Horm SV, Tarantola A, Rith S, Ly S, Gambaretti J, Duong V, et al. Intense circulation of A/H5N1 and other avian influenza viruses in Cambodian live-bird markets with serological evidence of sub-clinical human infections. Emerg Microbes Infect. 2016; doi: 10.1038/emi.2016.69 27436362

5. Nobusawa E, Sato K. Comparison of the Mutation Rates of Human Influenza A and B Viruses. J Virol. 2006;80: 3675–3678. doi: 10.1128/JVI.80.7.3675-3678.2006 16537638

6. Parvin JD, Moscona A, Pan WT, Leider JM, Palese P. Measurement of the mutation rates of animal viruses: influenza A virus and poliovirus type 1. J Virol. 1986;59: 377–383. 3016304

7. Pauly MD, Procario MC, Lauring AS. A novel twelve class fluctuation test reveals higher than expected mutation rates for influenza A viruses. Elife. 2017;6. doi: 10.7554/eLife.26437 28598328

8. Suárez P, Valcárcel J, Ortín J. Heterogeneity of the mutation rates of influenza A viruses: isolation of mutator mutants. J Virol. 1992;66: 2491–2494. 1548773

9. Baccam P, Beauchemin C, Macken CA, Hayden FG, Perelson AS. Kinetics of influenza A virus infection in humans. J Virol. 2006;80: 7590–7599. doi: 10.1128/JVI.01623-05 16840338

10. Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature. 2012;486: 420–428. doi: 10.1038/nature10831 22722205

11. Linster M, van Boheemen S, de Graaf M, Schrauwen EJA, Lexmond P, Mänz B, et al. Identification, Characterization, and Natural Selection of Mutations Driving Airborne Transmission of A/H5N1 Virus. Cell. 2014;157: 329–339. doi: 10.1016/j.cell.2014.02.040 24725402

12. Herfst S, Schrauwen EJA, Linster M, Chutinimitkul S, de Wit E, Munster VJ, et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science. 2012;336: 1534–1541. doi: 10.1126/science.1213362 22723413

13. Wilker PR, Dinis JM, Starrett G, Imai M, Hatta M, Nelson CW, et al. Selection on haemagglutinin imposes a bottleneck during mammalian transmission of reassortant H5N1 influenza viruses. Nat Commun. 2013;4: 2636. doi: 10.1038/ncomms3636 24149915

14. Russell CA, Fonville JM, Brown AEX, Burke DF, Smith DL, James SL, et al. The Potential for Respiratory Droplet–Transmissible A/H5N1 Influenza Virus to Evolve in a Mammalian Host. Science. 2012;336: 1541–1547. doi: 10.1126/science.1222526 22723414

15. Sigal D, Reid JNS, Wahl LM. Effects of Transmission Bottlenecks on the Diversity of Influenza A Virus. Genetics. 2018;210: 1075–1088. doi: 10.1534/genetics.118.301510 30181193

16. Imai H, Dinis JM, Zhong G, Moncla LH, Lopes TJS, McBride R, et al. Diversity of Influenza A(H5N1) Viruses in Infected Humans, Northern Vietnam, 2004–2010. Emerg Infect Dis. 2018;24: 1128–1238. doi: 10.3201/eid2407.171441 29912683

17. Welkers MRA, Pawestri HA, Fonville JM, Sampurno OD, Pater M, Holwerda M, et al. Genetic diversity and host adaptation of avian H5N1 influenza viruses during human infection. Emerg Microbes Infect. 2019;8: 262–271. doi: 10.1080/22221751.2019.1575700 30866780

18. Milani A, Fusaro A, Zamperin G, Bonfante F, Mancin M, Mastrorilli E, et al. Viral population diversity in vaccinated poultry host infected with H5N1 highly pathogenic avian influenza virus. Int J Infect Dis. 2016;53: 104.

19. Iqbal M, Xiao H, Baillie G, Warry A, Essen SC, Londt B, et al. Within-host variation of avian influenza viruses. Philos Trans R Soc Lond B Biol Sci. 2009;364: 2739–2747. doi: 10.1098/rstb.2009.0088 19687042

20. Gutiérrez RA, Viari A, Godelle B, Buchy P. Biased mutational pattern and quasispecies hypothesis in H5N1 virus. Infect Genet Evol. 2013;15: 69–76. doi: 10.1016/j.meegid.2011.10.019 22063822

21. Suttie A, Karlsson EA, Deng Y-M, Hurt AC, Greenhill AR, Barr IG, et al. Avian influenza in the Greater Mekong Subregion, 2003–2018. Infect Genet Evol. 2019;74: 103920. doi: 10.1016/j.meegid.2019.103920 31201870

22. Rith S, Davis CT, Duong V, Sar B, Horm SV, Chin S, et al. Identification of Molecular Markers Associated with Alteration of Receptor-Binding Specificity in a Novel Genotype of Highly Pathogenic Avian Influenza A(H5N1) Viruses Detected in Cambodia in 2013. J Virol. 2014;88: 13897–13909. doi: 10.1128/JVI.01887-14 25210193

23. Horwood PF, Karlsson EA, Horm SV, Ly S, Heng S, Chin S, et al. Circulation and characterization of seasonal influenza viruses in Cambodia, 2012–2015. Influenza Other Respi Viruses. 2019;13: 465–476.

24. Zhu H, Wang J, Wang P, Song W, Zheng Z, Chen R, et al. Substitution of lysine at 627 position in PB2 protein does not change virulence of the 2009 pandemic H1N1 virus in mice. Virology. 2010;401: 1–5. doi: 10.1016/j.virol.2010.02.024 20303563

25. Horwood PF, Horm SV, Suttie A, Thet S, Y P, Rith S, et al. Co-circulation of Influenza A H5, H7, and H9 Viruses and Co-infected Poultry in Live Bird Markets, Cambodia. Emerg Infect Dis. 2018;24: 352–355. doi: 10.3201/eid2402.171360 29350140

26. Zhou B, Donnelly ME, Scholes DT, St George K, Hatta M, Kawaoka Y, et al. Single-reaction genomic amplification accelerates sequencing and vaccine production for classical and Swine origin human influenza a viruses. J Virol. 2009;83: 10309–10313. doi: 10.1128/JVI.01109-09 19605485

27. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9: 357–359. doi: 10.1038/nmeth.1923 22388286

28. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30: 2114–2120. doi: 10.1093/bioinformatics/btu170 24695404

29. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25: 2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

30. Koboldt DC, Chen K, Wylie T, Larson DE, McLellan MD, Mardis ER, et al. VarScan: variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics. 2009;25: 2283–2285. doi: 10.1093/bioinformatics/btp373 19542151

31. Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22: 568–576. doi: 10.1101/gr.129684.111 22300766

32. Elbe S, Buckland-Merrett G. Data, disease and diplomacy: GISAID’s innovative contribution to global health. Global Challenges. 2017;1: 33–46. doi: 10.1002/gch2.1018 31565258

33. Shu Y, McCauley J. GISAID: Global initiative on sharing all influenza data–from vision to reality. Eurosurveillance. 2017;22: 30494. doi: 10.2807/1560-7917.ES.2017.22.13.30494 28382917

34. Zhang Y, Aevermann BD, Anderson TK, Burke DF, Dauphin G, Gu Z, et al. Influenza Research Database: An integrated bioinformatics resource for influenza virus research. Nucleic Acids Res. 2017;45: D466–D474. doi: 10.1093/nar/gkw857 27679478

35. Hadfield J, Megill C, Bell SM, Huddleston J, Potter B, Callender C, et al. Nextstrain: real-time tracking of pathogen evolution. Kelso J, editor. Bioinformatics. 2018;34: 4121–4123. doi: 10.1093/bioinformatics/bty407 29790939

36. Katoh K, Misawa K, Kuma KK-I, Miyata T. MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res. 2002;30: 3059–3066. doi: 10.1093/nar/gkf436 12136088

37. Nguyen L-T, Schmidt HA, von Haeseler A, Minh BQ. IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol. 2015;32: 268–274. doi: 10.1093/molbev/msu300 25371430

38. Chernomor O, von Haeseler A, Minh BQ. Terrace Aware Data Structure for Phylogenomic Inference from Supermatrices. Syst Biol. 2016;65: 997–1008. doi: 10.1093/sysbio/syw037 27121966

39. Sagulenko P, Puller V, Neher RA. TreeTime: Maximum-likelihood phylodynamic analysis. Virus Evolution. 2018;4. doi: 10.1093/ve/vex042 29340210

40. Nelson CW, Moncla LH, Hughes AL. SNPGenie: estimating evolutionary parameters to detect natural selection using pooled next-generation sequencing data. Bioinformatics. 2015;31: 3709–3711. doi: 10.1093/bioinformatics/btv449 26227143

41. Nei M, Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol. 1986;3: 418–426. doi: 10.1093/oxfordjournals.molbev.a040410 3444411

42. Sorn S, Sok T, Ly S, Rith S, Tung N, Viari A, et al. Dynamic of H5N1 virus in Cambodia and emergence of a novel endemic sub-clade. Infect Genet Evol. 2013;15: 87–94. doi: 10.1016/j.meegid.2012.05.013 22683363

43. Yamada S, Suzuki Y, Suzuki T, Le MQ, Nidom CA, Sakai-Tagawa Y, et al. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature. 2006;444: 378–382. doi: 10.1038/nature05264 17108965

44. Yang Z-Y, Wei C-J, Kong W-P, Wu L, Xu L, Smith DF, et al. Immunization by avian H5 influenza hemagglutinin mutants with altered receptor binding specificity. Science. 2007;317: 825–828. doi: 10.1126/science.1135165 17690300

45. Wang M, Tscherne DM, McCullough C, Caffrey M, García-Sastre A, Rong L. Residue Y161 of influenza virus hemagglutinin is involved in viral recognition of sialylated complexes from different hosts. J Virol. 2012;86: 4455–4462. doi: 10.1128/JVI.07187-11 22301136

46. Suguitan AL, Matsuoka Y, Lau Y-F, Santos CP, Vogel L, Cheng LI, et al. The multibasic cleavage site of the hemagglutinin of highly pathogenic A/Vietnam/1203/2004 (H5N1) avian influenza virus acts as a virulence factor in a host-specific manner in mammals. J Virol. 2012;86: 2706–2714. doi: 10.1128/JVI.05546-11 22205751

47. Schrauwen EJA, Herfst S, Leijten LM, van Run P, Bestebroer TM, Linster M, et al. The multibasic cleavage site in H5N1 virus is critical for systemic spread along the olfactory and hematogenous routes in ferrets. J Virol. 2012;86: 3975–3984. doi: 10.1128/JVI.06828-11 22278228

48. Zhou H, Yu Z, Hu Y, Tu J, Zou W, Peng Y, et al. The Special Neuraminidase Stalk-Motif Responsible for Increased Virulence and Pathogenesis of H5N1 Influenza A Virus. Martin DP, editor. PLoS One. 2009;4: e6277. doi: 10.1371/journal.pone.0006277 19609439

49. Zhou H, Jin M, Chen H, Huag Q, Yu Z. Genome-sequenee Analysis of the Pathogenic H5N1 Avian Influenza A Virus Isolated in China in 2004. Virus Genes. 2006;32: 85–95. doi: 10.1007/s11262-005-5849-9 16525739

50. Matsuoka Y, Swayne DE, Thomas C, Rameix-Welti M-A, Naffakh N, Warnes C, et al. Neuraminidase Stalk Length and Additional Glycosylation of the Hemagglutinin Influence the Virulence of Influenza H5N1 Viruses for Mice. J Virol. 2009;83: 4704–4708. doi: 10.1128/JVI.01987-08 19225004

51. Hatta M, Gao P, Halfmann P, Kawaoka Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science. 2001;293: 1840–1842. doi: 10.1126/science.1062882 11546875

52. Zhao L, Illingworth CJR. Measurements of intrahost viral diversity require an unbiased diversity metric. Virus Evol. 2019;5: vey041. doi: 10.1093/ve/vey041 30723551

53. Subbarao EK, Kawaoka Y, Murphy BR. Rescue of an influenza A virus wild-type PB2 gene and a mutant derivative bearing a site-specific temperature-sensitive and attenuating mutation. J Virol. 1993;67: 7223–7228. 8230444

54. Le QM, Sakai-Tagawa Y, Ozawa M, Ito M, Kawaoka Y. Selection of H5N1 influenza virus PB2 during replication in humans. J Virol. 2009;83: 5278–5281. doi: 10.1128/JVI.00063-09 19264775

55. Gabriel G, Dauber B, Wolff T, Planz O, Klenk H-D, Stech J. The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A. 2005;102: 18590–18595. doi: 10.1073/pnas.0507415102 16339318

56. Steel J, Lowen AC, Mubareka S, Palese P. Transmission of Influenza Virus in a Mammalian Host Is Increased by PB2 Amino Acids 627K or 627E/701N. Baric RS, editor. PLoS Pathog. 2009;5: e1000252. doi: 10.1371/journal.ppat.1000252 19119420

57. Soh YQS, Moncla LH, Eguia R, Bedford T, Bloom JD. Comprehensive mapping of adaptation of the avian influenza polymerase protein PB2 to humans. Elife. 2019;8. doi: 10.7554/eLife.45079 31038123

58. Auewarakul P, Suptawiwat O, Kongchanagul A, Sangma C, Suzuki Y, Ungchusak K, et al. An avian influenza H5N1 virus that binds to a human-type receptor. J Virol. 2007;81: 9950–9955. doi: 10.1128/JVI.00468-07 17626098

59. Naughtin M, Dyason JC, Mardy S, Sorn S, von Itzstein M, Buchy P. Neuraminidase inhibitor sensitivity and receptor-binding specificity of Cambodian clade 1 highly pathogenic H5N1 influenza virus. Antimicrob Agents Chemother. 2011;55: 2004–2010. doi: 10.1128/AAC.01773-10 21343450

60. Lyons DM, Lauring AS. Mutation and epistasis in influenza virus evolution [Internet]. Viruses 2018. doi: 10.3390/v10080407 30081492

61. Visher E, Whitefield SE, McCrone JT, Fitzsimmons W, Lauring AS. The Mutational Robustness of Influenza A Virus. PLoS Pathog. 2016;12: e1005856. doi: 10.1371/journal.ppat.1005856 27571422

62. Sanjuán R. Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis studies. Philos Trans R Soc Lond B Biol Sci. 2010;365: 1975–1982. doi: 10.1098/rstb.2010.0063 20478892

63. Watanabe Y, Ibrahim MS, Ellakany HF, Kawashita N, Mizuike R, Hiramatsu H, et al. Acquisition of Human-Type Receptor Binding Specificity by New H5N1 Influenza Virus Sublineages during Their Emergence in Birds in Egypt. Fouchier RAM, editor. PLoS Pathog. 2011;7: e1002068. doi: 10.1371/journal.ppat.1002068 21637809

64. Guilligay D, Tarendeau F, Resa-Infante P, Coloma R, Crepin T, Sehr P, et al. The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol. 2008;15: 500–506. doi: 10.1038/nsmb.1421 18454157

65. Nerome R, Hiromoto Y, Fukushima T, Nerome K, Lim W, Yamazaki Y, et al. Evolutionary characterization of the six internal genes of H5N1 human influenza A virus. J Gen Virol. 2000;81: 1293–1303. doi: 10.1099/0022-1317-81-5-1293 10769072

66. Xu L, Bao L, Zhou J, Wang D, Deng W, Lv Q, et al. Genomic Polymorphism of the Pandemic A (H1N1) Influenza Viruses Correlates with Viral Replication, Virulence, and Pathogenicity In Vitro and In Vivo. Digard P, editor. PLoS One. 2011;6: e20698. doi: 10.1371/journal.pone.0020698 21698272

67. Bussey KA, Desmet EA, Mattiacio JL, Hamilton A, Bradel-Tretheway B, Bussey HE, et al. PA Residues in the 2009 H1N1 Pandemic Influenza Virus Enhance Avian Influenza Virus Polymerase Activity in Mammalian Cells. J Virol. 2011;85: 7020–7028. doi: 10.1128/JVI.00522-11 21561908

68. Hiromoto Y, Saito T, Lindstrom S, Nerome K. Characterization of Low Virulent Strains of Highly Pathogenic A/Hong Kong/156/97 (H5N1) Virus in Mice after Passage in Embryonated Hens’ Eggs. Virology. 2000;272: 429–437. doi: 10.1006/viro.2000.0371 10873787

69. Webster RG, Govorkova EA, Kaverin NV, Varich NL, Gitelman AK, Lipatov AS, et al. Structure of antigenic sites on the haemagglutinin molecule of H5 avian influenza virus and phenotypic variation of escape mutants. J Gen Virol. 2002;83: 2497–2505. doi: 10.1099/0022-1317-83-10-2497 12237433

70. Yen H-L, Aldridge JR, Boon ACM, Ilyushina NA, Salomon R, Hulse-Post DJ, et al. Changes in H5N1 influenza virus hemagglutinin receptor binding domain affect systemic spread. Proc Natl Acad Sci U S A. 2009;106: 286–291. doi: 10.1073/pnas.0811052106 19116267

71. Stevens J, Blixt O, Chen L-M, Donis RO, Paulson JC, Wilson IA. Recent Avian H5N1 Viruses Exhibit Increased Propensity for Acquiring Human Receptor Specificity. J Mol Biol. 2008;381: 1382–1394. doi: 10.1016/j.jmb.2008.04.016 18672252

72. Wang W, Lu B, Zhou H, Suguitan AL, Cheng X, Subbarao K, et al. Glycosylation at 158N of the hemagglutinin protein and receptor binding specificity synergistically affect the antigenicity and immunogenicity of a live attenuated H5N1 A/Vietnam/1203/2004 vaccine virus in ferrets. J Virol. 2010;84: 6570–6577. doi: 10.1128/JVI.00221-10 20427525

73. Chutinimitkul S, van Riel D, Munster VJ, van den Brand JMA, Rimmelzwaan GF, Kuiken T, et al. In vitro assessment of attachment pattern and replication efficiency of H5N1 influenza A viruses with altered receptor specificity. J Virol. 2010;84: 6825–6833. doi: 10.1128/JVI.02737-09 20392847

74. Stevens J, Blixt O, Tumpey TM, Taubenberger JK, Paulson JC, Wilson IA. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science. 2006;312: 404–410. doi: 10.1126/science.1124513 16543414

75. Maines TR, Chen L-M, Van Hoeven N, Tumpey TM, Blixt O, Belser JA, et al. Effect of receptor binding domain mutations on receptor binding and transmissibility of avian influenza H5N1 viruses. Virology. 2011;413: 139–147. doi: 10.1016/j.virol.2011.02.015 21397290

76. Chen L-M, Blixt O, Stevens J, Lipatov AS, Davis CT, Collins BE, et al. In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity. Virology. 2012;422: 105–113. doi: 10.1016/j.virol.2011.10.006 22056389

77. Weber F, Kochs G, Gruber S, Haller O. A Classical Bipartite Nuclear Localization Signal on Thogoto and Influenza A Virus Nucleoproteins. Virology. 1998;250: 9–18. doi: 10.1006/viro.1998.9329 9770415

78. Grantham ML, Wu W-H, Lalime EN, Lorenzo ME, Klein SL, Pekosz A. Palmitoylation of the influenza A virus M2 protein is not required for virus replication in vitro but contributes to virus virulence. J Virol. 2009;83: 8655–8661. doi: 10.1128/JVI.01129-09 19553312

79. Holsinger LJ, Shaughnessy MA, Micko A, Pinto LH, Lamb RA. Analysis of the posttranslational modifications of the influenza virus M2 protein. J Virol. 1995;69: 1219–1225. 7529332

80. Li Y, Yamakita Y, Krug RM. Regulation of a nuclear export signal by an adjacent inhibitory sequence: The effector domain of the influenza virus NS1 protein. Proceedings of the National Academy of Sciences. 1998;95: 4864–4869.

81. Hale BG, Barclay WS, Randall RE, Russell RJ. Structure of an avian influenza A virus NS1 protein effector domain. Virology. 2008;378: 1–5. doi: 10.1016/j.virol.2008.05.026 18585749

82. Imai H, Shinya K, Takano R, Kiso M, Muramoto Y, Sakabe S, et al. The HA and NS Genes of Human H5N1 Influenza A Virus Contribute to High Virulence in Ferrets. Basler CF, editor. PLoS Pathog. 2010;6: e1001106. doi: 10.1371/journal.ppat.1001106 20862325

Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens

2020 Číslo 1

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Význam nemocničního alert systému v době SARS-CoV-2
nový kurz
Autoři: doc. MUDr. Helena Lahoda Brodská, Ph.D., prim. MUDr. Václava Adámková

Snímatelné zubní náhrady a fixační krémy
Autoři: doc. MUDr. Hana Hubálková, Ph.D.

Subkutánní imunoglobuliny v léčbě sekundárních imunodeficitů (reálná praxe)

Tofacitinib v terapii ulcerózní kolitidy
Autoři: prof. MUDr. Milan Lukáš, CSc.

Hereditární TTR amyloidoza - vzácné nebo jen neodhalené onemocnění? – 1. díl

Všechny kurzy
Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se