(A) A switch in receptor binding preference from avian-like (α2,3-linked sialic acid) to human-like (α2,6-linked sialic acid) receptors. The human form on the left shows the typical distribution of human adapted influenza viruses determined by their receptor binding preference for a2,6, linked SA that is predominantly expressed in the upper respiratory tract but also in the lungs. The human form on the right shows that infection with avian influenza viruses is concentrated in the lungs where their preferred a2,3 linked SA receptor is expressed. (B) Lower HA pH of activation and increased polymerase complex efficiency. Free-floating viruses that enter the human respiratory tract (upper part of figure) encounter mucus and a mildly acidic extracellular environment that act as innate barriers to virus infection. If NA is able to desialylate decoy receptors on mucus and HA has a sufficiently low pH of activation, then the virus particle may reach the apical surface of the respiratory epithelium intact. There through a multiplicity of interactions between HA and cell-surface sialic acid, the virus enters the target cell. After the virus is internalized, it passes through the endosomal pathway where the pH is progressively decreased. The low pH of the endosomal environment triggers an irreversible conformational change in HA that fuses the viral and endosomal membranes and ultimately results in the release of virus genetic material in the form of the viral ribonucleoprotein complex (vRNP) into the cell cytoplasm. The eight vRNPs are subsequently imported into the cell nucleus by interactions between the vRNPs and cellular nuclear import machinery. Inside the nucleus the virus polymerase complex replicates the virus genome in conjunction with co-opted cell proteins.