Substitutions in the PB2 methionine 283 residue affect H5 subtype avian influenza virus virulence

The influenza A virus (IAV) PB2 subunit modulates viral polymerase activity, replication kinetics and pathogenicity. Here we identified novel PB2 substitutions at position 283 of H5 subtype IAV and evaluated their biological characteristics and virulence. The substitution PB2-M283L enhanced the growth capacity and polymerase activity in human and mammalian cells in comparison to the rWT virus. The substitution PB2-M283L displayed high virulence, resulting in a greater virus load in different tissues, more severe histopathological lesions and proinflammatory cytokines burst in mice. The substitution PB2-M283I had an opposite phenotype. Our data extend the important role of PB2 substitutions in the adaptation of H5 subtype IAVs to mammalian hosts.