The complete sequence of the non-structural (NS) gene segment of the 1918 virus was deduced and also tested for the hypothesis that enhanced virulence in 1918 could have been due to type I interferon inhibition by the NS1 protein. The genotypic basis of this virulence has not yet been elucidated. The complete 1918 virus was even more virulent in mice. Using reverse genetics approaches, influenza virus constructs containing the 1918 HA and NA on a modern human influenza virus background were lethal in mice. Neither the 1918 hemagglutinin (HA) nor the neuraminidase (NA) genes possess mutations known to increase tissue tropicity that account for the virulence of other influenza virus strains like A/WSN/33 or the highly pathogenic avian influenza H5 or H7 viruses. The relationship of the 1918 virus with avian influenza viruses is further supported by recent work in which the 1918 hemagglutinin (HA) protein crystal structure was resolved. This finding supports the hypotheses that (1) the pandemic virus contains genes derived from avian-like influenza virus strains and that (2) the 1918 virus is the common ancestor of human and classical swine H1N1 influenza viruses. Sequence and phylogenetic analysis of the completed 1918 influenza virus genes shows them to be the most avian-like among the mammalian-adapted viruses. Using fixed and frozen lung tissue of 1918 influenza victims, the complete genomic sequence of the 1918 influenza virus has been deduced. The “Spanish” influenza pandemic of 1918–19 caused acute illness in 25–30 percent of the world’s population and resulted in the death of up to an estimated 40 million people.
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