The 2nd sialic acid-binding site of influenza A virus neuraminidase is an important determinant of the hemagglutinin-neuraminidase-receptor balance.
Animals
Binding Sites
Chlorocebus aethiops
Dogs
Humans
Influenza A Virus, H2N2 Subtype
/ chemistry
Influenza A Virus, H3N2 Subtype
/ chemistry
Madin Darby Canine Kidney Cells
N-Acetylneuraminic Acid
/ genetics
Neuraminidase
/ chemistry
Receptors, Virus
/ chemistry
Vero Cells
Viral Proteins
/ chemistry
Virion
/ chemistry
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
03
01
2019
accepted:
22
05
2019
revised:
20
06
2019
pubmed:
11
6
2019
medline:
4
12
2019
entrez:
11
6
2019
Statut:
epublish
Résumé
Influenza A virus (IAV) neuraminidase (NA) receptor-destroying activity and hemagglutinin (HA) receptor-binding affinity need to be balanced with the host receptor repertoire for optimal viral fitness. NAs of avian, but not human viruses, contain a functional 2nd sialic acid (SIA)-binding site (2SBS) adjacent to the catalytic site, which contributes to sialidase activity against multivalent substrates. The receptor-binding specificity and potentially crucial contribution of the 2SBS to the HA-NA balance of virus particles is, however, poorly characterized. Here, we elucidated the receptor-binding specificity of the 2SBS of N2 NA and established an important role for this site in the virion HA-NA-receptor balance. NAs of H2N2/1957 pandemic virus with or without a functional 2SBS and viruses containing this NA were analysed. Avian-like N2, with a restored 2SBS due to an amino acid substitution at position 367, was more active than human N2 on multivalent substrates containing α2,3-linked SIAs, corresponding with the pronounced binding-specificity of avian-like N2 for these receptors. When introduced into human viruses, avian-like N2 gave rise to altered plaque morphology and decreased replication compared to human N2. An opposite replication phenotype was observed when N2 was combined with avian-like HA. Specific bio-layer interferometry assays revealed a clear effect of the 2SBS on the dynamic interaction of virus particles with receptors. The absence or presence of a functional 2SBS affected virion-receptor binding and receptor cleavage required for particle movement on a receptor-coated surface and subsequent NA-dependent self-elution. The contribution of the 2SBS to virus-receptor interactions depended on the receptor-binding properties of HA and the identity of the receptors used. We conclude that the 2SBS is an important and underappreciated determinant of the HA-NA-receptor balance. The rapid loss of a functional 2SBS in pandemic viruses may have served to balance the novel host receptor-repertoire and altered receptor-binding properties of the corresponding HA protein.
Identifiants
pubmed: 31181126
doi: 10.1371/journal.ppat.1007860
pii: PPATHOGENS-D-18-02468
pmc: PMC6586374
doi:
Substances chimiques
Receptors, Virus
0
Viral Proteins
0
NA protein, influenza A virus
EC 3.2.1.18
Neuraminidase
EC 3.2.1.18
N-Acetylneuraminic Acid
GZP2782OP0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1007860Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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