MRC National Institute for Medical Research, London
Science for Health
Dating the origin of the 1918 influenza pandemic virus
01 October 2009
The 1918 influenza pandemic killed over 50 million people worldwide, making it the deadliest pandemic in recorded history. Understanding how it arose is an important goal of influenza research. The natural reservoir of the influenza A virus is waterfowl, where it causes little or no disease. These avian viruses do not usually infect humans as they are not adapted to the human host. Periodically, however, human influenza viruses may acquire gene segments from an avian virus giving rise to a global pandemic. The 1957-8 and the 1968-9 flu pandemics were caused by this process. Whether the 1918-19 (H1N1) virus originated directly from an avian reservoir has been hotly debated.
It has been noticed that influenza viruses show marked differences in nucleotide composition in mammalian and avian hosts. The evolution of base composition in different hosts can be modelled using Markov theory, allowing the time of the host shift from birds to mammals to be determined. This approach should be less susceptible to statistical noise and systematic bias than previous protein-based analyses.
Mario dos Reis, working in the lab of Richard Goldstein (pictured) in NIMR's Division of Mathematical Biology, and Alan Hay, Director of NIMR's World Influenza Centre, have analysed base composition and the phylogenetic relationships of several full genome sequences of H1N1 influenza viruses isolated from waterfowl, human and swine hosts.
Their model suggests that the sequence segments which eventually became the 1918 viral genome were introduced from birds into a mammalian host around 1882-1913 . The viruses later diverged into the classical swine and human H1N1 influenza lineages around 1913-15. The last common ancestor of human strains dates from February 1917 to April 1918, the upper date of introduction into the human population. Their model indicates that the 1918 virus did not originate directly from birds, and was most likely a swine flu, with parallels to the current 2009 pandemic.
Consensus tree for 1,000 bootstrap replicates
Click image to view at full-size
Support values for the mammalian virus clades are shown. The avian viruses are mostly from waterfowl except for a pigeon isolate. Inset figure: The date of the host shift avian-to-mammal was calculated from the observed G+C decay in mammalian viruses (blue and red dots). G+C composition in birds is high and stable (black dots). Influenza B (green dots), which has been established in humans for a long time, shows low G+C composition.
It has been suggested that the H1N1 classical swine lineage of influenza originated from a human source during the 1918-19 outbreak. Our results, however, strongly indicate that this lineage split from the human one about four years before the pandemic. The emergent pandemic H1N1 2009 virus is the first example, with the possible exception of 1918, that a virus of swine origin has become established in the human population to cause a pandemic. Certain parallels are apparent between the 1918 and 2009 pandemics, especially the possible role of swine as an intermediate host. The role of swine as a mixing vessel of different lineages, an important feature of the 2009 Swine-origin virus, is less clear with the 'Spanish flu' pandemic. While we find limited evidence that the 1918 human pandemic was the result of a human/swine reassortment, this might have occurred for some of the segments. The possibility that the 2009 pandemic virus might increase in pathogenicity emphasizes the importance of understanding how the 1918 virus emerged and the basis of its extreme pathogenicity.
Richard Goldstein
Original article
The research findings are published in full in:
Mario dos Reis, Alan J. Hay, Richard A. Goldstein (2009)
Using non-homogeneous models of nucleotide substitution to identify host shift events: application to the origin of the 1918 Spanish influenza pandemic virus
Journal of Molecular Evolution, epub ahead of print Full text Open Access
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