The Battle Between Influenza and the Innate Immune Response in the Human Respiratory Tract

Nicholls, John M

Finally a distinctive feature of the 1918 H1N1 NS1 and of many avian strains (including H5N1) is a C-terminal Glu-Ser-Glu-Val (ESEV) binding motif for a PDZ domain that mediates protein interaction. This finding was identified by large-scale sequence analysis of viruses isolated from different bird and mammalian species [77] . The ESEV domain is mainly present in avian influenza viruses while human viruses have a conserved RSKV domain. Jackson and colleagues in 2008 used reverse genetics to insert these different motifs into the mouse adapted A/WSN/33 and found that the RSKV had a better survival and lower viral load than the ESEV motif [78] . Later studies by Soubries and colleagues used LPAI H7N1 with a C-terminal RSKV and different species of cells and animals (ducks and mice), and found the changes in replication between ESEV and RSKV were species specific. In particular ESEV induced higher levels of IFN than RSKV in mouse cells but this ESKV was less sensitive to type 1 interferon pre-treatment [79] . The same groups also recently studied H7N1 HPAI with a deletion of 6 amino acids R225VESEV230 that was present in recent strains affecting poultry and found that the C-terminal ESEV domain did not increase virulence as deletion of the six amino acids had no impact on viral replication or immune response [80] . It should be noted that the 2008 H1N1 virus also has a stop codon at 220, thus suggesting that it behaves similar to H7N1 with the six amino acid deletion.