Rare binding of avian influenza viruses was detected in the trachea of pigs [64], which contrasts with the reported presence of sialic acids with α2,3 linkage to galactose as determined by lectin histochemistry [60]. Conversely, avian influenza viruses were shown to abundantly bind to alveolar macrophages [64], whereas expression of sialic acids learn more with α2,3 linkage to galactose was not detected [59]. Furthermore, evidence of HPAIV H5N1

infection of respiratory epithelial cells in the upper respiratory tract and trachea of humans, as determined by immunohistochemistry on cultures of human tissues infected ex vivo [71] and on tissues from fatal human cases [72] contrasts with no or rare binding of lectin and avian influenza virus in these tissues. There may be several reasons for this lack of consensus on the target cells for avian influenza viruses in the human respiratory tract. First, the attachment

patterns of lectins used in find protocol lectin histochemistry studies are variable, and depend on the lectin isoform and pre-treatment regimens applied to the cells or tissues [73]. Second, the specificity of influenza virus for the glycan receptor on the host cell is determined not only by the type of glycan-sialic acid linkage, but also by glycan modifications such as fucosylation, sulphation, and additional sialylation [74] and [75] and thus cannot be determined by techniques

that only measure glycan-sialic acid linkages. Third, the respiratory cells or tissues tested in these studies differed in their history and origin, which may have a non-negligible effect on receptor expression on the cell surfaces. Therefore, further research is required to determine the affinity of avian and other influenza viruses for different parts of the human respiratory tract and other organs, calling for standardization of the methodology used to determine the distribution of target cells. The accessibility of receptors for virus attachment at the portal second of entry in humans is essential for successful cross-species transmission of influenza viruses from animal reservoirs to humans. Target cells for avian influenza viruses are most abundant in deeper regions of the respiratory tract [64]. Inhaled droplets of small size deposit abundantly in these regions [76] and may harbour and deposit influenza virus particles in the vicinity of target cells for attachment. However, mucins secreted by mucous cells along the respiratory tract can bind to and trap avian influenza virus particles, and the ciliated respiratory epithelium continuously propels particles away from the lower respiratory tract.