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

TLDR

Influenza A viruses threaten humans by crossing species barriers, requiring polymerase adaptation to the host importin‑α protein that transports viral components into the nucleus. The authors investigated how individual importin‑α isoforms influence influenza virus replication, host specificity, and pathogenicity by using importin‑α‑silenced cells and knockout mice. Avian influenza viruses rely on importin‑α3 for polymerase and nucleoprotein function, whereas mammalian viruses depend on importin‑α7, and H1N1v uses both, indicating that importin‑α specificity dictates host range and interspecies transmission.

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. Interspecies transmission of influenza A viruses requires adaptation of the viral polymerase to the host importin-α. Here, the polymerase subunit PB2 and the nucleoprotein of avian viruses are found to require importin-α3, whereas mammalian viruses are shown to require importin-α7.