The origin and virulence of the 1918 "Spanish" influenza virus

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.

Figure 1

Life expectancy in the United States, 1900–60, showing the impact of the 1918 influenza pandemic (Grove and Hetzel 1968; Linder and Grove 1943; United States Department of Commerce 1976).

Figure 2

Influenza and pneumonia mortality by age, United States. Influenza and pneumonia specific mortality by age, including an average of the inter-pandemic years 1911–15 (dashed line), and the pandemic year 1918 (solid line). Specific death rate is per 100,000 of the population in each age division (Grove and Hetzel 1968; Linder and Grove 1943; United States Department of Commerce 1976).

Figure 3

Influenza and pneumonia mortality by age (solid line), with influenza morbidity by age (dashed line) superimposed. Influenza and pneumonia mortality by age as in figure 2. Specific death rate per age group, left ordinal axis. Influenza morbidity presented as ratio of incidence in persons of each group to incidence in persons of all ages (=100), right ordinal axis. Horizontal line at 100 (right ordinal axis) represents average influenza incidence in the total population (Taubenberger et al. 2001; adapted from Jordan 1927).

Figure 4

Change in hemagglutinin (HA) and neuraminidase (NA) proteins over time (Reid et al. 1999; Reid et al. 2000; Taubenberger et al. 2000). The number of amino acid changes from a hypothetical ancestor was plotted versus the date of viral isolation for viruses isolated from 1930 to 1993. Open circles, human HA; closed diamonds, human NA; closed circles, swine HA; open diamonds, swine NA. Regression lines were drawn and extrapolated to the x-intercept and then the 1918 data points (closed square, 1918 HA; closed circle, 1918 NA) were added to the graph (arrow).

Figure 5

Phylogenetic tree of the influenza virus hemagglutinin gene segment. Amino acid changes in three lineages of the influenza virus hemagglutinin protein segment, HA1. The tree shows the numbers of unambiguous changes between these sequences, with branch lengths being proportional to number of changes.