From July 1998 to August 2020, at least 69 people worldwide were infected with H9N2 viruses. It is noteworthy that the long-term prevalence favors the interspecies transmission of H9N2 viruses from avian species to humans. For decades, H9N2 viruses have evolved to break through the interspecies barrier transmitting to pigs, dogs, horses, mink, pika, and bats. H9N2 is one of the most widespread subtypes of the AIV family, which has been found in wild birds and as an enzootic pathogen in poultry across much of Asia and parts of Africa since 1966. They not only cause serious economic damage to the global poultry industry, but also occasionally pose substantial threats to human health. Collectively, these data demonstrate that residues 226 and 227 are under selective pressure and their synergistic regulation of receptor avidity and antigenicity is related to the evolution of circulating H9N2 viruses.ДЄvian influenza viruses (AIVs) belong to the genus Alphainfluenzavirus of the virus family Orthomyxoviridae. Among the four naturally-occurring amino acid combinations comprising QQ, MQ, LQ, and LM, the number of viruses with LM accounted for 79.64% of the sublineage h9.4.2.5 and the rescued virus with LM exhibited absolute advantages of in vitro and in vivo replication and transmission.

Further analysis suggested that increased receptor avidity facilitated by residue 226Q or 227M resulted in a reduction in the HI titer. The antigenic map based on the cross-hemagglutination inhibition (HI) titers revealed that amino acid substitutions at positions 226 or 227 appear to be involved in antigenic drift, potentially resulting in the emergence of H9N2 immune evasion mutants. Consequently, each of these two successive residues can modulate the receptor avidity of H9N2 viruses and influence their potential of zoonotic infection.

The solid-phase direct binding assay showed that residue 226 plays a core role in the receptor preference of H9N2 viruses, while residue 227 affects the preference of the virus for a receptor. In this study, we determined the effects of the flexibility at residues 226 and 227 in the hemagglutinin on the receptor avidity and immune evasion of H9N2 viruses. In particular, the emerging sublineage h9.4.2.5 of H9N2 viruses has drawn great attention. The enzootic and zoonotic nature of H9N2 avian influenza viruses poses a persistent threat to the global poultry industry and public health.

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