Academic journal article Proceedings of the American Philosophical Society

The Origin and Virulence of the 1918 "Spanish" Influenza Virus1

Academic journal article Proceedings of the American Philosophical Society

The Origin and Virulence of the 1918 "Spanish" Influenza Virus1

Article excerpt

ABSTRACT.

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. Using fixed and frozen lung tissue of 1918 influenza victims, the complete genomic sequence of the 1918 influenza virus has been deduced. Sequence and phylogenetic analysis of the completed 1918 influenza virus genes shows them to be the most avian-like among the mammalian-adapted viruses. 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. 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. 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. Using reverse genetics approaches, influenza virus constructs containing the 1918 HA and NA on a modern human influenza virus background were lethal in mice. The complete 1918 virus was even more virulent in mice. The genotypic basis of this virulence has not yet been elucidated. 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. Results from these experiments suggest that in human cells the 1918 NS1 is a very effective interferon antagonist, but the 1918 NS1 gene does not have the amino acid change that correlates with virulence in the H5N1 virus strains identified in 1997 in Hong Kong. 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 elucidate how pandemic influenza virus strains emerge and what genetic features contribute to virulence in humans.

INFLUENZA A VIRUSES are negative strand RNA viruses of the genus Orthomyxoviridae. They continually circulate in humans in yearly epidemics (mainly in the winter in temperate climates) and antigenically novel virus strains emerge sporadically as pandemic viruses (Cox and Subbarao 2000). In the United States, influenza is estimated to kill 30,000 people in an average year (Simonsen et al. 2000; Thompson et al. 2003). Every few years, influenza epidemics boost the annual number of deaths past the average, causing 10-15,000 additional deaths. Occasionally, and unpredictably, influenza sweeps the world, infecting 20 percent to 40 percent of the population in a single year. In these pandemic years, the numbers of deaths can be dramatically above average. In 1957-58, a pandemic was estimated to cause 66,000 excess deaths in the United States (Simonsen et al. 1998). In 1918, the worst pandemic in recorded history was associated with approximately 675,000 total deaths in the United States (United States Department of Commerce 1976), and killed an estimated 40 million people worldwide (Crosby 1989; Johnson and Mueller 2002; Patterson and PyIe 1991).

Influenza A viruses constantly evolve by the mechanisms of antigenie drift and shift (Webster et al. 1992). Consequently, they should be considered emerging infectious disease agents, perhaps "continually" emerging pathogens. The importance of predicting the emergence of new circulating influenza virus strains for subsequent annual vaccine development cannot be overestimated (Gensheimer et al. 1999). Pandemic influenza viruses have emerged three times in this century: in 1918 ("Spanish" influenza, HlNl), in 1957 ("Asian" influenza, H2N2), and in 1968 ("Hong Kong" influenza, H3N2; Cox and Subbarao 2000; Webby and Webster 2003). …

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