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Mutation of the Second Sialic Acid-Binding Site, Resulting in Reduced Neuraminidase Activity, Preceded the Emergence of H7N9 Influenza A Virus. | LitMetric

AI Article Synopsis

  • The novel influenza A virus (IAV) H7N9, emerging since 2013, raises concerns about its capacity for human transmission due to altered receptor-binding properties in its H7 protein.
  • Analysis revealed that a specific mutation (T401A) in the N9 neuraminidase (NA) protein enhances enzymatic activity by affecting substrate binding, a process typically thought to occur after changes in hemagglutinin (HA).
  • These findings suggest that mutations in the NA protein may facilitate the evolution of receptor-binding properties in HA, contributing to the ongoing health threat posed by H7N9 viruses in humans.

Article Abstract

The emergence of the novel influenza A virus (IAV) H7N9 since 2013 has caused concerns about the ability of the virus to spread between humans. Analysis of the receptor-binding properties of the H7 protein of a human isolate revealed modestly increased binding to α2,6 sialosides and reduced, but still dominant, binding to α2,3-linked sialic acids (SIAs) compared to a closely related avian H7N9 virus from 2008. Here, we show that the corresponding N9 neuraminidases (NAs) display equal enzymatic activities on a soluble monovalent substrate and similar substrate specificities on a glycan array. In contrast, solid-phase activity and binding assays demonstrated reduced specific activity and decreased binding of the novel N9 protein. Mutational analysis showed that these differences resulted from substitution T401A in the 2nd SIA-binding site, indicating that substrate binding via this site enhances NA catalytic activity. Substitution T401A in the novel N9 protein appears to functionally mimic the substitutions that are found in the 2nd SIA-binding site of NA proteins of avian-derived IAVs that became human pandemic viruses. Our phylogenetic analyses show that substitution T401A occurred prior to substitutions in hemagglutinin (HA), causing the altered receptor-binding properties mentioned above. Hence, in contrast to the widespread assumption that such changes in NA are obtained only after acquisition of functional changes in HA, our data indicate that mutations in the 2nd SIA-binding site may have enabled and even driven the acquisition of altered HA receptor-binding properties and may have contributed to the spread of the novel H7N9 viruses. Novel H7N9 IAVs continue to cause human infections and pose an ongoing public health threat. Here, we show that their N9 proteins display reduced binding to and lower enzymatic activity against multivalent substrates, resulting from mutation of the 2nd sialic acid-binding site. This mutation preceded and may have driven the selection of substitutions in H7 that modify H7 receptor-binding properties. Of note, all animal IAVs that managed to cross the host species barrier and became human viruses carry mutated 2nd sialic acid-binding sites. Screening of animal IAVs to monitor their potential to cross the host species barrier should therefore focus not only on the HA protein, but also on the functional properties of NA.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391454PMC
http://dx.doi.org/10.1128/JVI.00049-17DOI Listing

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