Highly Pathogenic H5N1 and Novel H7N9 Influenza A Viruses Induce More Profound Proteomic Host Responses than Seasonal and Pandemic H1N1 Strains

Influenza
A viruses (IAV) are important human and animal pathogens
with potential for causing pandemics. IAVs exhibit a wide spectrum
of clinical illness in humans, from relatively mild infections by
seasonal strains to acute respiratory distress syndrome during infections
with some highly pathogenic avian influenza (HPAI) viruses. In the
present study, we infected A549 human cells with seasonal H1N1 (sH1N1),
2009 pandemic H1N1 (pdmH1N1), or novel H7N9 and HPAI H5N1 strains.
We used multiplexed isobaric tags for relative and absolute quantification
to measure proteomic host responses to these different strains at
1, 3, and 6 h post-infection. Our analyses revealed that both H7N9
and H5N1 strains induced more profound changes to the A549 global
proteome compared to those with low-pathogenicity H1N1 virus infection,
which correlates with the higher pathogenicity these strains exhibit
at the organismal level. Bioinformatics analysis revealed important
modulation of the nuclear factor erythroid 2-related factor 2 (NRF2)
oxidative stress response in infection. Cellular fractionation and
Western blotting suggested that the phosphorylated form of NRF2 is
not imported to the nucleus in H5N1 and H7N9 virus infections. Fibronectin
was also strongly inhibited in infection with H5N1 and H7N9 strains.
This is the first known comparative proteomic study of the host response
to H7N9, H5N1, and H1N1 viruses and the first time NRF2 is shown to
be implicated in infection with highly pathogenic strains of influenza.