A review of influenza haemagglutinin receptor binding as it relates to pandemic properties

Abstract

Haemagglutinin is a determinant of many viral properties, and successful adaptation to a human-like form is thought to be an important step toward pandemic influenza emergence. The availability of structurally distinct sialic acid linked receptors in the sites of human and avian influenza infection are generally held to account for the differences observed, but the relevance of other selection pressures has not been elucidated. There is evidence for genetic and structural constraints of haemagglutinin playing a role in restricting haemagglutinin adaptation, and also for differences in the selection pressure to alter binding, specifically when considering virus replication within host compared to transmission between hosts. Understanding which characteristics underlie such adaptations in humans is now possible in greater detail by using glycan arrays. However, results from these assays must also interpreted in context of an as yet still to be determined detailed knowledge of the structural diversity of sialic acids in the human respiratory tract. A clearer understanding of the evolutionary benefits conveyed by different haemagglutinin properties would have substantial impact and would affect the risk we allocate to viral propagation in different species, such as swine and poultry. Relevant to the H5N1 threat, current evidence also suggests that mortality associated with any emergent pandemic from current strains may be reduced if haemagglutinin specificity changes, further emphasising the importance of understanding how and if selection pressures in the human will cause such an alteration.

Figure 1. The role of HA in steps to productive human infection

1. Evasion of acquired immunity, through novel antigenic features. 2. Avoidance of innate immunity, including possible loss of 'decoy' receptor binding to mucin. 3. Productive SA binding, specifically to a2–6 linkages prevalent in the human upper respiratory tract. 4. Effective membrane fusion. 5. Efficient viral budding, for example through an appropriate "HA/NA balance".

Figure 2. Reactivity of human respiratory tissues with lectins specific for different sialic acid linkages

Res, respiratory bronchiole (adjacent to alveoli); Ter, terminal bronchiole (distal to alveoli); Alv, alveolus. The green shows reaction with Sambucus nigra lectin, which indicates the presence of sialic acid linked to galactose by an α2–6-linkage. The red shows reaction with Maackia amurensis lectin, indicating the presence of sialic acid linked to galactose by an α2–6-linkage. (Reprinted by permission from Macmillan Publishers Ltd: images reproduced from Shinya et al. 2006 [29])

Figure 3. The cone-like (left) and umbrella-like (right) topologies presented by Chandrasekaran et al.

The umbrella conformation is unique to sialic acids with an α2–6 linkage and chains of sufficient length. As illustrated above, the topology is alleged to result from both the angle constrained by the linkage and the open spread allowed by the longer chain. (Reprinted by permission from Macmillan Publishers Ltd: Chandrasekaran et al. Nat Biotechnol 2008 Jan;26(1):107–13).

Figure 4. Lectin staining in the pig trachea

M. amurensis lectin was used to detect SA with α2–3 linkages, while S. nigra was used to detect SA with α2–6 linkages. The green and orange in the images indicates both are present in the pig trachea. Blue staining in the connective tissue represents autofluorescence. (Image reproduced from Ito et al. 1998 with permission from American Society for Microbiology [46])

Figure 5. Attachment of H5N1 virus to regions of the human respiratory tract

Red is representative of viral binding, which is shown to increase with depth in the respiratory tract. Image reproduced from van Riel et al. 2007 [42] with permission from Elsevier)