Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 38, Issue 6, Pages 817-826Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.b15-00120
Keywords
influenza virus; sialidase; low-pH stability; virus replication; pandemic
Categories
Funding
- MEXT/JSPS KAKENHI [18390142, 23590549, 20790357, 26670064]
- CREST (Japan Science and Technology Agency)
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- SRI (Shizuoka Research Institute)
- Research Foundation for the Electro-technology of Chubu
- Global COE Program from the Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [20790357, 18390142, 15H05644, 26670064] Funding Source: KAKEN
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The spike glycoprotein neuraminidase (NA) of influenza A virus (IAV) has sialidase activity that cleaves the terminal sialic acids (viral receptors) from oligosaccharide chains of glycoconjugates. A new antigenicity of viral surface glycoproteins for humans has pandemic potential. We found low-pH stability of sialidase activity in NA. The low-pH stability can maintain sialidase activity under acidic conditions of pH 4-5. For human IAVs, NAs of all pandemic viruses were low-pH-stable, whereas those of almost all human seasonal viruses were not. The low-pH stability was dependent on amino acid residues near the active site, the calcium ion-binding site, and the subunit interfaces of the NA homotetramer, suggesting effects of the active site and the homotetramer on structural stability. IAVs with the low-pH-stable NA showed much higher virus replication rates than those of IAVs with low-pH-unstable NA, which was correlated with maintenance of sialidase activity under an endocytic pathway of the viral cell entry mechanism, indicating contribution of low-pH stability to high replication rates of pandemic viruses. The low-pH-stable NA of the 1968 H3N2 pandemic virus was derived from the low-pH-stable NA of H2N2 human seasonal virus, one of two types classified by both low-pH stability in N2 NA and a phylogenetic tree of N2 NA genes. The 2009 H1N1 pandemic virus acquired low-pH-stable NA by two amino acid substitutions at the early stage of the 2009 pandemic. It is thought that low-pH stability contributes to infection spread in a pandemic through enhancement of virus replication.
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