Abstract
The hemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza A virus are responsible for the surface interactions of the virion with the host. Entry of the virus is mediated by functions of the HA: binding to cellular receptors and facilitating fusion of the virion membrane with the endosomal membrane. The HA structure contains receptor binding sites in the globular membrane distal head domains of the trimer, and the fusion machinery resides in the stem region. These sites have specific characteristics associated with subtype and host, and the differences often define species barriers. For example, avian viruses preferentially recognize α2,3-Sialic acid terminating glycans as receptors and mammalian viruses recognize α2,6-Sialic acid. The neuraminidase, or the receptor-destroying protein, cleaves the sialic acid from cellular membrane constituents and viral glycoproteins allowing for egress of nascent virions. A functional balance of activity has been demonstrated between the two glycoproteins, resulting in an optimum level of HA affinity and NA enzymatic cleavage to allow for productive infection. As more is understood about both HA and NA, the relevance for functional balance between HA and NA continues to expand, with potential implications for interspecies transmission, host adaptation, and pathogenicity.
Highlights
Influenza viruses are members of the Orthomyxoviridae family and all share the genomic make-up of single stranded, segmented, negative sense RNA
Influenza pandemics caused by antigenically novel strains, arise at unpredictable intervals and can occur outside the seasonal norms, sometimes affecting alternative subgroups of the population such as young healthy adults. For both seasonal and pandemic influenza, the infection is established in the upper respiratory tract, but disease severity can vary significantly depending on a range of viral and host factors
A growing body of evidence highlights the significance for optimal functional balance between the HA and its companion viral envelope protein, the neuraminidase (NA) in the context of entry and egress, and it is likely that this balance impacts the processes of transmission, host range and pathogenicity as well
Summary
Influenza viruses are members of the Orthomyxoviridae family and all share the genomic make-up of single stranded, segmented, negative sense RNA. A major determinant of high pathogenicity involves polybasic insertion sequences in the hemagglutinin (HA) of certain strains that allow for cleavage activation of infectivity by proteases expressed intracellularly in various tissues of the host, facilitating systemic infection [10,11,12] To date, such strains have been restricted to subsets of H5 and H7 subtype avian viruses, and, examples of limited avian to human transmission by direct contact have been reported, these have been self-limiting [13,14,15,16]. To understand the complex nature of influenza ecology and cross-species transmission, it is critical to explore in-depth the nature of HA and NA glycan recognition and the identity and distribution of natural glycan receptors in the cells and tissues of their avian, mammalian, and human hosts
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