Similar to the H1 HA receptor binding site [10], two sets of human receptor binding residues provide networks to make contact with the long human-type receptor that results in an umbrella-like topology of the receptor. (i) A base region Neu5Acα2,6Galβ1- motif is governed by residues 131–138 in a 130-loop, residues 140–145 in a 140-loop and residues 219–228 in a 220-loop [163]. Figure 3b shows direct H-bond formation between Y98, G135, S136, N137, H183, E190 and S228 in the pdm H3/1968 binding site and Sia-1 of 6′SLNLN. In the human H3/2007 binding site, Y98, T135, S136, S137, S228, R222, and N225 make direct H-bonds with Sia-1 and Gal-2, respectively, of 6′SLNLN. (ii) The extension region -4GlcNAcβ1,4Galβ1,4GlcNAc motif is governed by residues 190–196 in a 190-helix and residues 156–160 in a 150-loop [163], and S193 and K156 in the pdm H3/1968 binding site were observed to generate direct H-bonds with GlcNAc-5 of 6′SLNLN. Amino acid change in HA during co-evolution with humans occurs to evade human immunity. Not only is there a change in antigenicity but the number of glycosylation sites masking antigenicity also increases over time as shown in Figure 3c; the numbers of glycosylation sites/monomer are two for avian H3/1968 HA, two for pdm H3/1968 HA, seven for human H3/2007 HA and six for human H3/2014. The limitation of increase in the number of glycosylation sites might be because the change of the virus must have a balance between mutation and selection for optimal immune evasion and infection. Taken together, the change in receptor binding specificity of long-term circulating human IAVs from short and long to long α2,6 sialylated glycans may have resulted from aa change in the RBS (Figure 3b,d) and an increase in glycosylation sites surrounding the RBS, possibly making the shallow RBS deeper (Figure 3c). The differences in receptor binding preferences of avian, pandemic and long-term circulating human IAVs are associated with viral pathology along the human respiratory tract containing different sialylated glycan structures. The preferential binding of avian and pandemic viruses to both short and extended receptors can typically cause diffuse alveolar damage, resulting in greater severity than that caused by long-term circulating human viruses with preference for long receptors that rarely infect human alveoli [164,165]. This correlates well with our finding that human alveolar N-glycans consist of mainly short receptors, 22.32: 0.17: 16.10: 0.15 mol% (Neu5Acα2,3LN: Neu5Acα2,3(α1,3fucosylated LN): Neu5Acα2,6LN: Neu5Ac-LN-LN), of total human alveolar N-glycans [19]. Sialyl N-glycans with various numbers of LN units (up to 10 units) have been reported in human lungs (principally terminated in α2,3Neu5Ac [166]) and the human bronchus, whereas fewer extended LN profiles can be detected in the human nasopharynx [167]. Although structures of glycans in the human trachea have not be determined, the pdm H1N1/2009 virus was found at higher levels in tracheal aspirate specimens than in throat or nasopharyngeal swabs [168]. Uncomplicated long-term circulating human viruses are related to tracheobronchitis [169].