Abstract
ABSTRACT Influenza virus haemagglutinin (HA) and neuraminidase (NA) are involved in the recognition and modulation of sialic acids on the cell surface as the virus receptor. Although the balance between two proteins functions has been found to be crucial for viral fitness, the interplay between the proteins has not been well established. Herein we present evidence for interplay between influenza HA and NA, which may affect the balance between two glycoprotein functions. NA enzymatic activities against sialoglycans were promoted by the presence of HA, which is in accordance with the level of co-existing HA. Such activity enhancement was lost when the HA-receptor binding properties were abolished by low-pH treatment or by mutations at the HA receptor binding domain. Sialidase activities of NA-containing virus-like particles and native influenza viruses were detected using different NA-assays and sialic acid substrates. Most pronounced HA-mediated NA enhancement was found when intact virions were confronted with multivalent surface-anchored substrates, which mimics the physiological conditions on cell membranes. Using recombinant viruses with altered HA bindings preference between α2,3- and α2,6-linked sialic acids, we also found that NA function against different substrates is correlated with the HA-receptor specificity. The effect of HA-receptor specificities on NA functions, together with the HA-mediated NA enhancement, may play a role in virus evasion of the mucus barrier, as well as in cross-species adaptation. Our data also indicate the importance of using multivalent substrates in future studies of NA functions.
Highlights
Influenza A viruses continue to circulate in humans and in various animal species including birds, pigs, horses and dogs [1]
Enzymatic activities of N1-virus-like particles (VLPs) and native H1N1pdm viruses were measured by serial dilutions in an NA-Star assay, and the two preparations were normalized for their cleavage activities against the NA-Star substrate (Figure 1(A))
Sialic acid molecules on the host cell surface are regarded as the influenza virus receptors that interact with both HA and NA [3]
Summary
Influenza A viruses continue to circulate in humans and in various animal species including birds, pigs, horses and dogs [1]. Human influenza pandemics arise when novel subtypes of influenza viruses emerge from animals through genetic reassortment and in the past these spread within months across the world, leading to large numbers of deaths. Two major surface glycoproteins of influenza viruses, the haemagglutinin (HA) and neuraminidase (NA), both recognize the host-cell sialic acid (SA) molecules as the influenza virus receptor [3]. Influenza HA is a trimeric protein which binds to host cell SA-receptors as the initial step of virus attachment [5,6]. Upon virus entry into host cell via endocytosis, the acidic environment of the endosome induces a conformational change in HA that exposes the fusion peptide, allowing for viral-endosomal fusion. NA plays a role in the initial stage of virus infection by facilitating virus motility on the cell surface [10]
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