Decoding the Distribution of Glycan Receptors for Human-Adapted Influenza A Viruses in Ferret Respiratory Tract

Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Department of Biological Engineering, Cambridge, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2012; 7(2):e27517. DOI: 10.1371/journal.pone.0027517
Source: PubMed


Ferrets are widely used as animal models for studying influenza A viral pathogenesis and transmissibility. Human-adapted influenza A viruses primarily target the upper respiratory tract in humans (infection of the lower respiratory tract is observed less frequently), while in ferrets, upon intranasal inoculation both upper and lower respiratory tract are targeted. Viral tropism is governed by distribution of complex sialylated glycan receptors in various cells/tissues of the host that are specifically recognized by influenza A virus hemagglutinin (HA), a glycoprotein on viral surface. It is generally known that upper respiratory tract of humans and ferrets predominantly express α2→6 sialylated glycan receptors. However much less is known about the fine structure of these glycan receptors and their distribution in different regions of the ferret respiratory tract. In this study, we characterize distribution of glycan receptors going beyond terminal sialic acid linkage in the cranial and caudal regions of the ferret trachea (upper respiratory tract) and lung hilar region (lower respiratory tract) by multiplexing use of various plant lectins and human-adapted HAs to stain these tissue sections. Our findings show that the sialylated glycan receptors recognized by human-adapted HAs are predominantly distributed in submucosal gland of lung hilar region as a part of O-linked glycans. Our study has implications in understanding influenza A viral pathogenesis in ferrets and also in employing ferrets as animal models for developing therapeutic strategies against influenza.

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    • "This could enable preliminary assessment of pandemic potential of newly emerged influenza strains by providing an estimation of their affinity for human sialic acid receptors and their ability to be neutralized by existing anti-HA antibodies. Use of our structural model of Hangzhou-H7 for docking analysis predicted that it had a similar affinity for the human α2,6 sialyl-lactose receptor (−6.9 kcal/mol) than the avian α2,3 sialyl-lactose receptor (−6.6 kcal/mol), which could suggest increased pandemic potential [21], [47]. When assessed using the same model, the HA of the high pathogenicity avian H7N7 strain showed a higher affinity for the avian than the human receptor, as might be expected of a non-mammalian adapted strain. "
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    • "The distribution of terminal Sias in α2-6 and in α2-3 linkages varies along the respiratory tract, and changes with age and developmental stage [19,23]. Human respiratory tract sialylation patterns have been extensively studied on paraffin embedded tissues, which are lacking much of the secreted mucus layer [23,24]. Here we examine glycosylation and IAV binding to frozen human trachea/bronchus tissues that were frozen and embedded in optimal cutting temperature (OCT) compound. "
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    • "The transmissibility of human-adapted pandemic influenza strains, 1918 H1N1, 1957 H2N2 and 2009 H1N1, in ferrets has been demonstrated to correlate with the specificity and quantitative affinity of the viral surface glycoprotein hemagglutinin (HA) binding to α2→6 sialylated glycans (or human receptors) [7]–[9]. These human receptors are predominantly expressed in the respiratory tract epithelium of humans and ferrets [10]–[12]. The HA of influenza viruses isolated from avian species typically binds to α2→3 sialylated glycans (or avian receptors) [11]. "
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