Abstract
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.
Highlights
An important determinant of influenza A virus pathogenesis is the tropism of virus in terms of the specific tissues and cell types that it infects in different host species
The host tissue or cell tropism of the viruses have been investigated previously using in vitro pattern of viral adherence (PVA) to tissues from humans and other model animal systems or by staining of fixed ex vivo tissue sections with viruses [1,2]. These studies demonstrated that human-adapted influenza viruses such as H1N1 and H3N2 subtypes bind to human upper respiratory tissues, whereas avian-adapted viruses such as H5N1 bind to human deeplung and gastrointestinal tract and avian respiratory tissues [1,2]
Upon intranasal inoculation of the virus, ferrets exhibit similar clinical manifestation as that of humans there seems to be a difference in viral tropism between ferrets and humans
Summary
An important determinant of influenza A virus pathogenesis is the tropism of virus in terms of the specific tissues and cell types that it infects in different host species. The host tissue or cell tropism of the viruses have been investigated previously using in vitro pattern of viral adherence (PVA) to tissues from humans and other model animal systems or by staining of fixed ex vivo tissue sections with viruses [1,2] These studies demonstrated that human-adapted influenza viruses (which show highly efficient respiratory droplet transmission and high pathogenicity in humans) such as H1N1 and H3N2 subtypes bind to human upper respiratory tissues (tracheal/bronchial), whereas avian-adapted viruses (which circulate among birds and have gross pathogenicity only in birds) such as H5N1 bind to human deeplung and gastrointestinal tract and avian respiratory tissues [1,2]. Viral binding and infection is observed predominantly in the upper respiratory tract [7], whereas in ferrets, it is observed in lower respiratory tract ( in the hilar regions and not as much in the alveolar regions) [8,9,10]
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