Abstract
The initial recognition between influenza virus and the host cell is mediated by interactions between the viral surface protein hemagglutinin and sialic acid-terminated glycoconjugates on the host cell surface. The sialic acid residues can be linked to the adjacent monosaccharide by α2-3- or α2-6-type glycosidic bonds. It is this linkage difference that primarily defines the species barrier of the influenza virus infection with α2-3 binding being associated with avian influenza viruses and α2-6 binding being associated with human strains. The ferret has been extensively used as an animal model to study the transmission of influenza. To better understand the validity of this model system, we undertook glycomic characterization of respiratory tissues of ferret, which allows a comparison of potential viral receptors to be made between humans and ferrets. To complement the structural analysis, lectin staining experiments were performed to characterize the regional distributions of glycans along the respiratory tract of ferrets. Finally, the binding between the glycans identified and the hemagglutinins of different strains of influenza viruses was assessed by glycan array experiments. Our data indicated that the respiratory tissues of ferret heterogeneously express both α2-3- and α2-6-linked sialic acids. However, the respiratory tissues of ferret also expressed the Sda epitope (NeuAcα2-3(GalNAcβ1-4)Galβ1-4GlcNAc) and sialylated N,N'-diacetyllactosamine (NeuAcα2-6GalNAcβ1-4GlcNAc), which have not been observed in the human respiratory tract surface epithelium. The presence of the Sda epitope reduces potential binding sites for avian viruses and thus may have implications for the usefulness of the ferret in the study of influenza virus infection.
Highlights
The ferret is a key animal model to study the transmission characteristics of influenza viruses
To understand how the glycosylation of ferret respiratory tissues differ from other animal models and humans, we demonstrate a comprehensive analysis of ferret upper and lower respiratory tract glycosylation
The low mass region of the spectrum was dominated by high mannose structures (m/z 1988, 2192, and 2396), whereas middle and high m/z regions consisted of molecular ions that were consistent with bi, tri, and tetra-antennary complex glycans, including structures with LacNAc repeats
Summary
The ferret is a key animal model to study the transmission characteristics of influenza viruses. Results: Characterization of ferret respiratory tract tissues identified influenza virus glycan receptors. The sialic acid residues can be linked to the adjacent monosaccharide by ␣2–3- or ␣2– 6-type glycosidic bonds It is this linkage difference that primarily defines the species barrier of the influenza virus infection with ␣2–3 binding being associated with avian influenza viruses and ␣2– 6 binding being associated with human strains. As an example of this restriction, previous studies suggested that avian viruses, especially highly pathogenic avian influenza of the H5 and H7 subtypes, should not be able to infect the human airway epithelium. The 1997 H5N1 outbreak, indicated that this paradigm was too simple as this highly pathogenic avian influenza (which showed a restricted ␣2–3-Sia binding) was able to directly infect human airways, leading to severe pulmonary disease, but was limited to human to human transmission. In an attempt to understand the mechanism of the severe disease caused by influenza, the ferret has been used as a model to explore the pathophysiology of the virus and host interac-
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