Influenza viruses under pulmonary pressure: emergence of human-type polymerase signatures

Highly pathogenic avian influenza viruses (HPAIV) with human-type polymerase signatures replicate to high-levels especially in the human lower respiratory tract (LRT) and often cause pneumonia and death. Yet, the selective pressure which drives the fixation of these polymerase signatures is unknown. Here, we show that dominant expression of the antiviral factor importin-a3 is a hallmark of the lung with particularly high expression levels in the LRT. However, H5N1 and H7N7 HPAIV with human-type polymerase signatures (PB2627K, PB2701N) are able to circumvent the inhibitory activity of importin-a3. This is achieved by high-level TNF-a induction which represses importin-a3 expression giving rise to high-level viral replication and virulence in the mammalian host. These findings suggest that PB2 polymorphisms evolve, at least in part, under an importin-a mediated selective pressure along the mammalian respiratory tract. Approaches that aim to recover inhibitory importin-a3 levels might pose a novel therapeutic basis to treat patients with pneumonia.