Alterations in hemagglutinin receptor-binding specificity accompany the emergence of highly pathogenic avian influenza viruses

Highly pathogenic avian influenza viruses (HPAIVs) of hemagglutinin H5 and H7 subtypes emerge after introduction of low pathogenic avian influenza viruses (LPAIVs) from wild birds into poultry flocks followed by subsequent circulation and evolution. The acquisition of multiple basic amino acids at the endoproteolytical cleavage site of the hemagglutinin (HA) is a molecular indicator for high pathogenicity, at least for infections of gallinaceous poultry. Apart from the well-studied significance of the multi-basic HA cleavage site there is only limited knowledge on other alterations in the HA and neuraminidase (NA) molecules associated with changes in tropism during emergence of HPAIVs from LPAIVs. We hypothesized that changes in tropism may require alterations of sialyloligosaccharide specificities of HA and NA. To test this hypothesis we compared a number of LPAIVs and HPAIVs for their HA-mediated binding and NA-mediated desialylation of a set of synthetic receptor analogs, namely, α2-3 sialylated oligosaccharides. NA substrate specificity correlated with structural groups of NAs and did not correlate with pathogenic potential of the virus. In contrast, all HPAIVs differed from LPAIVs by a higher HA receptor-binding affinity towards trisaccharides 3'SLN and SiaLec and by the ability to discriminate between non-fucosylated and fucosylated sialyloligosaccharides 3'SLN and SiaLex. These results suggest that alteration of the receptor-binding specificity accompanies emergence of the HPAIV from their low pathogenic precursors.