Identification of Rare PB2-D701N Mutation from a Patient with Severe Influenza: Contribution of the PB2-D701N Mutation to the Pathogenicity of Human Influenza

Overview

Journal Front Microbiol

Specialty Microbiology

Date 2017 Apr 20

PMID 28421062

Citations 7

Authors

Amelia Nieto

Francisco Pozo

Matxalen Vidal-Garcia

Manuel Omenaca

Inmaculada Casas

Ana Falcon

Affiliations

Soon will be listed here.

Abstract

Several amino acid changes have been previously implicated in adaptation of avian influenza viruses to human hosts, among them the D701N change in the PB2 polymerase subunit that also is the main determinant of avian virus pathogenesis in animal models. However, previous studies using recombinant viruses did not provide conclusive information of the contribution of this PB2 residue to pathogenicity in human influenza virus strains. We identified this mutation in an A(H1N1)pdm09-like human influenza virus isolated from an infected patient with pneumonia and acute respiratory failure, admitted to the intensive care unit. An exhaustive search has revealed PB2-D701 as a highly conserved position in all available H1N1 human virus sequences in NCBI database, showing a very low prevalence of PB2-D701N change. Presence of PB2-701N amino acid correlates with severe or fatal outcome in those scarce cases with known disease outcome of the infection. In these patients, the residue PB2-701N may contribute to pathogenicity as it was previously reported in humans infected with avian viruses. This study helps to clarify a debate that has arisen regarding the role of PB2-D701N in human influenza virus pathogenicity.

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References

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(2):429-37. DOI: 10.1006/viro.2000.0371. View

Webster R, BEAN W, Gorman O, Chambers T, Kawaoka Y . Evolution and ecology of influenza A viruses. Microbiol Rev. 1992; 56(1):152-79. PMC: 372859. DOI: 10.1128/mr.56.1.152-179.1992. View

Martinez-Romero C, de Vries E, Belicha-Villanueva A, Mena I, Tscherne D, Gillespie V . Substitutions T200A and E227A in the hemagglutinin of pandemic 2009 influenza A virus increase lethality but decrease transmission. J Virol. 2013; 87(11):6507-11. PMC: 3648128. DOI: 10.1128/JVI.00262-13. View

Hulse D, Webster R, Russell R, Perez D . Molecular determinants within the surface proteins involved in the pathogenicity of H5N1 influenza viruses in chickens. J Virol. 2004; 78(18):9954-64. PMC: 514963. DOI: 10.1128/JVI.78.18.9954-9964.2004. View

Xu C, Hu W, Xu K, He Y, Wang T, Chen Z . Amino acids 473V and 598P of PB1 from an avian-origin influenza A virus contribute to polymerase activity, especially in mammalian cells. J Gen Virol. 2011; 93(Pt 3):531-540. DOI: 10.1099/vir.0.036434-0. View

Li K, Guan Y, Wang J, Smith G, Xu K, Duan L . Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature. 2004; 430(6996):209-13. DOI: 10.1038/nature02746. View

Gabriel G, Czudai-Matwich V, Klenk H . Adaptive mutations in the H5N1 polymerase complex. Virus Res. 2013; 178(1):53-62. DOI: 10.1016/j.virusres.2013.05.010. View

Herfst S, Imai M, Kawaoka Y, Fouchier R . Avian influenza virus transmission to mammals. Curr Top Microbiol Immunol. 2014; 385:137-55. DOI: 10.1007/82_2014_387. View

Vasin A, Temkina O, Egorov V, Klotchenko S, Plotnikova M, Kiselev O . Molecular mechanisms enhancing the proteome of influenza A viruses: an overview of recently discovered proteins. Virus Res. 2014; 185:53-63. DOI: 10.1016/j.virusres.2014.03.015. View

10.

Mina M, Klugman K . The role of influenza in the severity and transmission of respiratory bacterial disease. Lancet Respir Med. 2014; 2(9):750-63. PMC: 4823014. DOI: 10.1016/S2213-2600(14)70131-6. View

11.

Horimoto T, Kawaoka Y . Influenza: lessons from past pandemics, warnings from current incidents. Nat Rev Microbiol. 2005; 3(8):591-600. DOI: 10.1038/nrmicro1208. View

12.

Song M, Pascua P, Lee J, Baek Y, Lee O, Kim C . The polymerase acidic protein gene of influenza a virus contributes to pathogenicity in a mouse model. J Virol. 2009; 83(23):12325-35. PMC: 2786751. DOI: 10.1128/JVI.01373-09. View

13.

Sorrell E, Schrauwen E, Linster M, de Graaf M, Herfst S, Fouchier R . Predicting 'airborne' influenza viruses: (trans-) mission impossible?. Curr Opin Virol. 2012; 1(6):635-42. PMC: 3311991. DOI: 10.1016/j.coviro.2011.07.003. View

14.

Subbarao E, LONDON W, Murphy B . A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol. 1993; 67(4):1761-4. PMC: 240216. DOI: 10.1128/JVI.67.4.1761-1764.1993. View

15.

Resa-Infante P, Jorba N, Coloma R, Ortin J . The influenza virus RNA synthesis machine: advances in its structure and function. RNA Biol. 2011; 8(2):207-15. PMC: 3127100. DOI: 10.4161/rna.8.2.14513. View

16.

Shinya K, Hamm S, Hatta M, Ito H, Ito T, Kawaoka Y . PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology. 2004; 320(2):258-66. DOI: 10.1016/j.virol.2003.11.030. View

17.

Yamayoshi S, Yamada S, Fukuyama S, Murakami S, Zhao D, Uraki R . Virulence-affecting amino acid changes in the PA protein of H7N9 influenza A viruses. J Virol. 2013; 88(6):3127-34. PMC: 3957961. DOI: 10.1128/JVI.03155-13. View

18.

Schrauwen E, Fouchier R . Host adaptation and transmission of influenza A viruses in mammals. Emerg Microbes Infect. 2015; 3(2):e9. PMC: 3944123. DOI: 10.1038/emi.2014.9. View

19.

Fodor E . The RNA polymerase of influenza a virus: mechanisms of viral transcription and replication. Acta Virol. 2013; 57(2):113-22. DOI: 10.4149/av_2013_02_113. View

20.

Mehle A, Dugan V, Taubenberger J, Doudna J . Reassortment and mutation of the avian influenza virus polymerase PA subunit overcome species barriers. J Virol. 2011; 86(3):1750-7. PMC: 3264373. DOI: 10.1128/JVI.06203-11. View