Human-specific Regulation of 2–6-linked Sialic Acids*□S

Many microbial pathogens and toxins recognize animal cells via cell surface sialic acids (Sias) that are 2–3or 2–8-linked to the underlying glycan chain. Human influenza A/B viruses are unusual in preferring 2–6linked Sias, undergoing a switch from 2–3 linkage preference during adaptation from animals to humans. This correlates with the expression of 2–6-linked Sias on ciliated human airway epithelial target cells and of 2– 3-linked Sias on secreted soluble airway mucins, which are unable to inhibit virus binding. Given several known differences in Sia biology between humans and apes, we asked whether this pattern of airway epithelial Sia linkages is also human-specific. Indeed, we show that since the last common ancestor with apes, humans underwent a concerted bidirectional switch in 2–6linked Sia expression between airway epithelial cell surfaces and secreted mucins. This can explain why the chimpanzee appears relatively resistant to experimental infection with human Influenza viruses. Other tissues showed additional examples of human-specific increases or decreases in 2–6-linked Sia expression and only one example of a change specific to certain great apes. Furthermore, while human and great ape leukocytes both express 2–6-linked Sias, only human erythrocytes have markedly up-regulated expression. These cell type-specific changes in 2–6-Sia expression during human evolution represent another example of a human-specific change in Sia biology. Because the data set involves multiple great apes, we can also conclude that Sia linkage expression patterns can be conserved during millions of years of evolution within some vertebrate taxa while undergoing sudden major changes in other closely related ones.