Neuraminidase activity and specificity of influenza A virus are influenced by haemagglutinin-receptor binding

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.

Neuraminidase antigenic drift of H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding

“…As such, studying the NA and HA proteins together is crucial to understanding viral evolution. Both the HA and the NA protein interact with the same ligand, sialic acid, and thus balancing each proteins' affinity for this ligand is critical to the influenza cycle [36][37][38][39]. Both proteins are necessary for in vivo replication, but the nuance of their interaction is important as well.…”

A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin

“…They pointed out that other viruses including influenza family viruses contain these sites that are easily spread among people (Huang et al, 2011;Menachery et al, 2014;Tang et al, 2020;Vlasak et al, 1988 ). But in these viruses, the site of activation is found on a protein called haemagglutinin, not on the SP (Bernstein et al, 2020;Koopman et al, 2019;Lai et al, 2019). However, some other researchers are more cautious about the significant role of the activation site in helping CoV and facilitating its spread (Amer et al, 2018;Van Doremalen et al, 2013).…”

Antiviral Activity of Chicken Cathelicidin B1 Against Influenza A Virus

“…HA functions as a receptor binding and fusion protein, while the NA protein is involed in release of (nascent) virus particles from decoy receptors or the cell surface (Gamblin and Skehel, 2010;Dou et al, 2018). Recently, it has been reported that NA activity of IAV is influenced by virus-receptor binding (Guo et al, 2018;Du et al, 2019;Lai et al, 2019). NA activity is altered based on enhanced or a reduced HA-receptor binding property.…”

“…Next we performed a solid phase cleavage (ELLA) assay using the glycoprotein fetuin. Cleavage of fetuin by NA in this assay depends on the activity of NA, but also on the activity of HA, as receptor-binding by HA contributes significantly to NA cleavage (Guo et al, 2018;Lai et al, 2019), at least when multivalent receptors are used. CATH-B1 inhibited cleavage of sialic acids on fetuin ( Figure 7B).…”