Mutation of the Second Sialic Acid-Binding Site, Resulting in Reduced Neuraminidase Activity, Preceded the Emergence of H7N9 Influenza A Virus
| Autor: | James C. Paulson, Ryan McBride, Raoul J. de Groot, Wenjie Peng, Frank J. M. van Kuppeveld, Meiling Dai, Mark J.G. Bakkers, Cornelis A. M. de Haan, J. C. F. M. Dortmans, Erik de Vries |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Immunology Hemagglutinin (influenza) Neuraminidase Hemagglutinin Glycoproteins Influenza Virus Sialic acid binding medicine.disease_cause Influenza A Virus H7N9 Subtype Microbiology Virus 03 medical and health sciences chemistry.chemical_compound Virology Influenza Human medicine Influenza A virus Humans Phylogeny chemistry.chemical_classification Mutation Binding Sites biology Sialic acid 030104 developmental biology Enzyme Biochemistry chemistry Genetic Diversity and Evolution Amino Acid Substitution Insect Science biology.protein Sialic Acids Receptors Virus Protein Binding |
| Zdroj: | Journal of Virology |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.00049-17 |
| Popis: | 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. IMPORTANCE 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. |
| Databáze: | OpenAIRE |
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