Neu5Gc binding loss of subtype H7 influenza A virus facilitates adaptation to gallinaceous poultry following transmission from waterbirds but restricts spillback.

Migratory waterfowl, gulls, and shorebirds are natural reservoirs for influenza A viruses that can occasionally spill over to domestic poultry, and ultimately humans. The molecular mechanisms underlying interspecies transmission and adaptation, particularly between wild birds and domestic poultry, remain poorly understood. This study showed wild-type H7 influenza A viruses from waterbirds initially bind to glycan receptors terminated with N-Acetylneuraminic acid (Neu5Ac) or N-Glycolylneuraminic acid (Neu5Gc). However, after enzootic transmission in chickens, the viruses exclusively bind to Neu5Ac. The absence of Neu5Gc expression in gallinaceous poultry, particularly chickens, exerts selective pressure, shaping influenza virus populations, and promoting the acquisition of adaptive amino acid substitutions in the hemagglutinin protein of H7 influenza A viruses. This results in the loss of Neu5Gc binding and an increase in virus transmissibility in gallinaceous poultry, particularly chickens. Consequently, the transmission capability of these poultry-adapted H7 viruses in wild water birds decreases. Timely intervention, such as stamping out, may help reduce virus adaptation to domestic chicken populations and lower the risk of enzootic outbreaks, including those caused by influenza A viruses exhibiting high pathogenicity.