The ''Spanish'' influenza pandemic of 1918 was characterized by exceptionally high mortality, especially among young adults. The surface proteins of influenza viruses, hemagglutinin and neuraminidase, play important roles in virulence, host specificity, and the human immune response. The complete coding sequence of hemagglutinin was reported last year. This laboratory has now determined the complete coding sequence of the neuraminidase gene of the 1918 virus. Influenza RNA fragments were isolated from lung tissue of three victims of the 1918 flu; complete sequence was generated from A͞Brevig Mission͞1͞18, with confirmatory sequencing carried out on A͞South Carolina͞1͞18 and A͞New York͞1͞18. The 1918 neuraminidase gene sequence was compared with other N1 subtype neuraminidase genes, including 9 N1 strains newly sequenced for this study. The 1918 neuraminidase shares many sequence and structural characteristics with avian strains, including the conserved active site, wild-type stalk length, glycosylation sites, and antigenic sites. Phylogenetically, the 1918 neuraminidase gene appears to be intermediate between mammals and birds, suggesting that it was introduced into mammals just before the 1918 pandemic.
The Spanish influenza pandemic of 1918-1919 caused acute illness in 25-30% of the world's population and resulted in the death of 40 million people. The complete genomic sequence of the 1918 influenza virus will be deduced using fixed and frozen tissues of 1918 influenza victims. Sequence and phylogenetic analyses of the complete 1918 haemagglutinin (HA) and neuraminidase (NA) genes show them to be the most avian-like of mammalian sequences and support the hypothesis that the pandemic virus contained surface protein-encoding genes derived from an avian influenza strain and that the 1918 virus is very similar to the common ancestor of human and classical swine H1N1 influenza strains. Neither the 1918 HA genes nor the NA genes possessed mutations that are known to increase tissue tropicity, which accounts for the virulence of other influenza strains such as A/WSN/33 or fowl plague viruses. The complete sequence of the nonstructural (NS) gene segment of the 1918 virus was deduced and tested for the hypothesis that the enhanced virulence in 1918 could have been due to type I interferon inhibition by the NS1 protein. The results from these experiments were inconclusive. Sequence analysis of the 1918 pandemic influenza virus is allowing us to test hypotheses as to the origin and virulence of this strain. This information should help to elucidate how pandemic influenza strains emerge and what genetic features contribute to their virulence.
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