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Differential use of importin-α isoforms governs cell tropism and host adaptation of influenza virus.

Gabriel G, Klingel K, Otte A, Thiele S, Hudjetz B, Arman-Kalcek G, Sauter M, Shmidt T, Rother F, Baumgarte S, Keiner B, Hartmann E, Bader M, Brownlee GG, Fodor E, Klenk HD - Nat Commun (2011)

Bottom Line: Influenza A viruses are a threat to humans due to their ability to cross species barriers, as illustrated by the 2009 H1N1v pandemic and sporadic H5N1 transmissions.In this study, we analysed replication, host specificity and pathogenicity of avian and mammalian influenza viruses, in importin-α-silenced cells and importin-α-knockout mice, to understand the role of individual importin-α isoforms in adaptation.Thus, differences in importin-α specificity are determinants of host range underlining the importance of the nuclear envelope in interspecies transmission.

View Article: PubMed Central - PubMed

Affiliation: 1] Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. [2] Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. [3] Institute of Virology, Philipps-University Marburg, Marburg, Germany.

ABSTRACT
Influenza A viruses are a threat to humans due to their ability to cross species barriers, as illustrated by the 2009 H1N1v pandemic and sporadic H5N1 transmissions. Interspecies transmission requires adaptation of the viral polymerase to importin-α, a cellular protein that mediates transport into the nucleus where transcription and replication of the viral genome takes place. In this study, we analysed replication, host specificity and pathogenicity of avian and mammalian influenza viruses, in importin-α-silenced cells and importin-α-knockout mice, to understand the role of individual importin-α isoforms in adaptation. For efficient virus replication, the polymerase subunit PB2 and the nucleoprotein (NP) of avian viruses required importin-α3, whereas PB2 and NP of mammalian viruses showed importin-α7 specificity. H1N1v replication depended on both, importin-α3 and -α7, suggesting ongoing adaptation of this virus. Thus, differences in importin-α specificity are determinants of host range underlining the importance of the nuclear envelope in interspecies transmission.

No MeSH data available.


Related in: MedlinePlus

Growth curves of various avian and human influenza viruses in importin-silenced human cells.Endogenous human importins (α1–α7) were silenced using siRNA in human lung cells (A549) and infected with (a) A/FPV/Rostock/1/34 (H7N7), (b) A/Thai/KAN-1/04 (H5N1), (c) A/Victoria/3/75 (H3N2), (d) A/Sachsen-Anhalt/101/09 (H1N1v) or (e) A/Hamburg/NY1580/09 (H1N1v). Growth curves show controls (black, filled diamonds), α1 (blue, squares), α3 (green, filled triangles), α4 (black, filled squares), α5 (black diamonds) and α7 (red triangles)-silenced cells.
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f3: Growth curves of various avian and human influenza viruses in importin-silenced human cells.Endogenous human importins (α1–α7) were silenced using siRNA in human lung cells (A549) and infected with (a) A/FPV/Rostock/1/34 (H7N7), (b) A/Thai/KAN-1/04 (H5N1), (c) A/Victoria/3/75 (H3N2), (d) A/Sachsen-Anhalt/101/09 (H1N1v) or (e) A/Hamburg/NY1580/09 (H1N1v). Growth curves show controls (black, filled diamonds), α1 (blue, squares), α3 (green, filled triangles), α4 (black, filled squares), α5 (black diamonds) and α7 (red triangles)-silenced cells.

Mentions: We have extended our studies to other avian and mammalian influenza viruses of different subtypes. Virus growth of the HPAIV A/FPV/Rostock/1/34 (H7N1) was restricted in importin-α3-silenced cells (Fig. 3a), whereas the HPAIV A/Thai/KAN-1/04 (H5N1) isolated from a lethal human case13 was not affected in importin-α3-silenced cells but reduced in importin-α7-silenced cells by 2 logs (Fig. 3b). Growth of the human A/Victoria/3/75 (H3N2) virus was also restricted in importin-α7-silenced cells (Fig. 3c). A/Sachsen-Anhalt/101/09 (H1N1v) and A/Hamburg/NY1580/09 (H1N1v) isolates from the 2009 pandemic were restricted in both importin-α3- and importin-α7-silenced cells (Fig. 3d,e). All viruses are dependent on importin-α1, whereas importin-α4 and -α5 appear to be redundant (Fig. 3). These data support the concept that human adaptation of influenza viruses is also associated with the acquisition of importin-α7 specificity.


Differential use of importin-α isoforms governs cell tropism and host adaptation of influenza virus.

Gabriel G, Klingel K, Otte A, Thiele S, Hudjetz B, Arman-Kalcek G, Sauter M, Shmidt T, Rother F, Baumgarte S, Keiner B, Hartmann E, Bader M, Brownlee GG, Fodor E, Klenk HD - Nat Commun (2011)

Growth curves of various avian and human influenza viruses in importin-silenced human cells.Endogenous human importins (α1–α7) were silenced using siRNA in human lung cells (A549) and infected with (a) A/FPV/Rostock/1/34 (H7N7), (b) A/Thai/KAN-1/04 (H5N1), (c) A/Victoria/3/75 (H3N2), (d) A/Sachsen-Anhalt/101/09 (H1N1v) or (e) A/Hamburg/NY1580/09 (H1N1v). Growth curves show controls (black, filled diamonds), α1 (blue, squares), α3 (green, filled triangles), α4 (black, filled squares), α5 (black diamonds) and α7 (red triangles)-silenced cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105303&req=5

f3: Growth curves of various avian and human influenza viruses in importin-silenced human cells.Endogenous human importins (α1–α7) were silenced using siRNA in human lung cells (A549) and infected with (a) A/FPV/Rostock/1/34 (H7N7), (b) A/Thai/KAN-1/04 (H5N1), (c) A/Victoria/3/75 (H3N2), (d) A/Sachsen-Anhalt/101/09 (H1N1v) or (e) A/Hamburg/NY1580/09 (H1N1v). Growth curves show controls (black, filled diamonds), α1 (blue, squares), α3 (green, filled triangles), α4 (black, filled squares), α5 (black diamonds) and α7 (red triangles)-silenced cells.
Mentions: We have extended our studies to other avian and mammalian influenza viruses of different subtypes. Virus growth of the HPAIV A/FPV/Rostock/1/34 (H7N1) was restricted in importin-α3-silenced cells (Fig. 3a), whereas the HPAIV A/Thai/KAN-1/04 (H5N1) isolated from a lethal human case13 was not affected in importin-α3-silenced cells but reduced in importin-α7-silenced cells by 2 logs (Fig. 3b). Growth of the human A/Victoria/3/75 (H3N2) virus was also restricted in importin-α7-silenced cells (Fig. 3c). A/Sachsen-Anhalt/101/09 (H1N1v) and A/Hamburg/NY1580/09 (H1N1v) isolates from the 2009 pandemic were restricted in both importin-α3- and importin-α7-silenced cells (Fig. 3d,e). All viruses are dependent on importin-α1, whereas importin-α4 and -α5 appear to be redundant (Fig. 3). These data support the concept that human adaptation of influenza viruses is also associated with the acquisition of importin-α7 specificity.

Bottom Line: Influenza A viruses are a threat to humans due to their ability to cross species barriers, as illustrated by the 2009 H1N1v pandemic and sporadic H5N1 transmissions.In this study, we analysed replication, host specificity and pathogenicity of avian and mammalian influenza viruses, in importin-α-silenced cells and importin-α-knockout mice, to understand the role of individual importin-α isoforms in adaptation.Thus, differences in importin-α specificity are determinants of host range underlining the importance of the nuclear envelope in interspecies transmission.

View Article: PubMed Central - PubMed

Affiliation: 1] Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. [2] Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. [3] Institute of Virology, Philipps-University Marburg, Marburg, Germany.

ABSTRACT
Influenza A viruses are a threat to humans due to their ability to cross species barriers, as illustrated by the 2009 H1N1v pandemic and sporadic H5N1 transmissions. Interspecies transmission requires adaptation of the viral polymerase to importin-α, a cellular protein that mediates transport into the nucleus where transcription and replication of the viral genome takes place. In this study, we analysed replication, host specificity and pathogenicity of avian and mammalian influenza viruses, in importin-α-silenced cells and importin-α-knockout mice, to understand the role of individual importin-α isoforms in adaptation. For efficient virus replication, the polymerase subunit PB2 and the nucleoprotein (NP) of avian viruses required importin-α3, whereas PB2 and NP of mammalian viruses showed importin-α7 specificity. H1N1v replication depended on both, importin-α3 and -α7, suggesting ongoing adaptation of this virus. Thus, differences in importin-α specificity are determinants of host range underlining the importance of the nuclear envelope in interspecies transmission.

No MeSH data available.


Related in: MedlinePlus