Role of receptor binding specificity in influenza A virus transmission and pathogenesis

Abstract

The recent emergence of a novel avian A/H7N9 influenza virus in poultry and humans in China, as well as laboratory studies on adaptation and transmission of avian A/H5N1 influenza viruses, has shed new light on influenza virus adaptation to mammals. One of the biological traits required for animal influenza viruses to cross the species barrier that received considerable attention in animal model studies, in vitro assays, and structural analyses is receptor binding specificity. Sialylated glycans present on the apical surface of host cells can function as receptors for the influenza virus hemagglutinin (HA) protein. Avian and human influenza viruses typically have a different sialic acid (SA)-binding preference and only few amino acid changes in the HA protein can cause a switch from avian to human receptor specificity. Recent experiments using glycan arrays, virus histochemistry, animal models, and structural analyses of HA have added a wealth of knowledge on receptor binding specificity. Here, we review recent data on the interaction between influenza virus HA and SA receptors of the host, and the impact on virus host range, pathogenesis, and transmission. Remaining challenges and future research priorities are also discussed.

Figure 1. Cartoon representation of the hemagglutinin structure of an H5N1 influenza A virus (protein database code 4KDO, representing a mutant version of A/Vietnam/1203/04)

The human receptor analog, LSTc (pink) is docked into the receptor binding site; the vestigial esterase subdomain and fusion peptide are depicted in yellow and orange, respectively. The amino acid substitutions described by Herfst et al are shown in red, and the mutations of Imai et al are shown in blue. Substitution Gln‐226‐Leu was described by both groups (Herfst et al, 2012; Imai et al, 2012).

Figure 2. N‐glycans, O‐glycans, and glycolipids

Examples of three types of N‐glycans are shown; complex with multiple N‐acetyllactosamine repeats (LN), oligomannose, and hybrid (with the common core boxed). A glycolipid and two types of O‐glycans are also shown; core 1 (in box) and core 2 (in box) O‐glycans. Monosaccharides are depicted using the following symbolic representations: fucose (red triangle), galactose (yellow circle), N‐acetyl glucosamine (blue square), N‐acetyl galactosamine (yellow square), glucosamine (blue circle), mannose (green circle), sialic acid (purple diamond).

Figure 3. Structures of Neu5Aca and Neu5Gc

Figure 4

Overall distribution of α2,6‐sialic acid (SA; red stars) and α2,3‐SA based on Maackia amurensis agglutinin (MAA)‐I (blue stars) and MAA‐II staining (yellow stars) in the epithelium of the respiratory tract (nasal cavity, trachea, bronchus, bronchiole, and alveoli) of humans (Nicholls et al, 2007a), ferrets (Xu et al, 2010a), pigs (Nelli et al, 2010), and chicken, and the small and large intestine of chickens (Costa et al, 2012). The size of the star shape corresponds with the relative receptor abundance. Receptor distribution may vary between studies, possibly due to the lectins used, experimental methods, or real variation in receptor distribution between animals. Lectin staining was not performed for the human trachea, nasal cavity of pigs and nasal cavity and bronchioles of ferrets in the cited studies. No MAA‐I staining was performed for the chicken tissues. Figure based on Herfst et al, 2012.

Figure 5

Cartoon representation of a human influenza hemagglutinin (database code 2YP4) receptor binding site with the 130‐loop, 190‐helix, and 220‐loop and the conserved residues, 98‐Tyr, 153‐Trp, 183‐His, and 195‐Tyr in complex with the human receptor analog LSTc in cis conformation (A). Amino acid alignment of the 130‐loop, 190‐helix, and 220‐loop of human (Hu), avian (Av), pig (Pi) influenza viruses, and an airborne transmissible H5N1 virus (Tr) (B). The sequences are derived from the following virus strains: A/Teal/NL/10/2000 (CY060178), A/Memphis/7/2001 (CY020149), A/SC/1/1918 (F116575), A/Mallard/SW/50/2000 (CY060308), A/HK/01/1968 (CY112249), A/Mallard/NL/5/1999 (CY064950), A/NL/056H1/1960 (CY077786), A/Indo/5/2005 (CY116646), airborne transmissible A/Indo/05/2005 (CY116686), A/Mallard/12/2000 (GU053030), A/NL/219/2003 (AY338459) and A/Shanghai/02/2013 (KF021597).

Figure 6. Human and avian receptor analogs in free conformation (Figure adapted from Xu et al, 2009)

Avian receptor analog LSTa is shown in trans conformation and the human receptor analog LSTc in cis conformation (A). Symbolic representation of the LSTa and LSTc structures (B), with the monosaccharides sialic acid (purple diamond), galactose (yellow circle), N‐acetylglucosamine (blue square) and glucose (blue circle).