The Spanish Flu Story

(UPDATE 15 Feb 06: Because so many people are finding their way to this post from Google and other search engines, I have reorganized the text to make it easier to read.)

Extending my earlier post "A Confluence of Concerns", on the potential for an epidemic from Avian Flu H5N1 and similarities between its emergence and the 1918 Flu:

James Newcomb at bio-era pointed me to a recent paper exploring the possible origins of the 1918 Spanish Flu.  In "A hypothesis: the conjunction of soldiers, gas, pigs, ducks, geese and horses in Northern France during the Great War provided the conditions for the emergence of the "Spanish" influenza pandemic of 1918-1919", Oxford et al. explore the hypothesis that this killer flu strain emerged at a large British Army camp in France during the Great War.

At the outset, the authors note that;

Four of the eight genes of influenza have now been sequenced and there is no clear genetic indication of why this virus was so virulent, though the NS1 gene-product may have played a role. Therefore, we need to examine the particular circumstances of 1918, such as population movements and major events of the time. Obviously, the unique circumstance of that period was the Great War. Could the special circumstances engendered in the war itself have allowed or caused the emergence, evolution and spread of a pandemic virus?

They go on to compile molecular, epidemiological, and historical evidence related to conditions in and around the base at Etaples, in Boulonge, which housed soldiers on the way to the front as well as large numbers of wounded brought by train directly from the front each night.  In particular, Oxford et al. note that more than one million soldiers moved through the camp by November 1917, with symptoms consistent with the flu appearing there as early as December 1916.  The camp is described as overcrowded, with the 100,000 troops quartered there housed in tents and temporary barracks.  There were numerous pigs, fowl, and horses in the vicinity, some of which were prepared for food by the troops themselves.  Finally, a great many of the troops in the area had been exposed to chemical weapons, some of them now known to be mutagenic.  That is, a large number of soldiers were living in very rough conditions, many of them with respiratory systems compromised by gas attacks, amidst animals known to carry viruses that jump to humans or recombine with viruses that we host.

So the conditions were ripe for more than one virus to be proliferate in immune compromised patients (taking the lungs as a component of the immune system), a necessary condition for recombination to take place within humans.  However, I find it particularly interesting that many of the gas weapons used in that area are mutagenic.  The authors note that no one has looked into the possibility that mustard gas, or any of the other weapons as far as I can tell, can "accelerate mutations in viruses such as influenza".

They conclude;

The evidence presented for 'seeding' of the 1918-1919 influenza pandemic up to 2 years earlier and the lack of a Chinese/Far East origin contains lessons for the future. In terms of advance planning for the next influenza pandemic, it should be recognised that it could emerge anywhere in the world when particular combinations of factors arise. The epicentre could be Hong Kong but it could equally be Saudi Arabia, Pakistan, Uruguay and other South American countries, Africa, Thailand and even some regions of modern day Europe. Influenza pandemic surveillance could be increased in all these regions.

So even if we don't see H5N1 emerge in Southeast Asia in the next year or so, that doesn't mean a strain that originates there won't become a problem elsewhere at a later date.  As for whether the conditions to create a killer strain in tsunami stricken regions are similar enough to the camp at  Etaples, it is probably not possible to draw many firm conclusions.  If a malaria outbreak occurs, then we may be in for trouble.  Yet the root cause of the transformations that brought the 1918 strain into being are still unclear; was it a recombination event or a series of mutations?  There are a number of papers that demonstrate that a key gene from the 1918 strain contain regions very similar to those in a strain that infects pigs.

However, the question of mutation or recombination seems to hinge on the assumptions used to construct models of the the lineage of the virus.  The origin of the hemagglutinin gene (HA) is, in particular, critical to sorting out how the bug came about because HA is the protein that enables viruses to bind to host cells and initiate infection.  It is also the primary viral target for the host immune system.  Thus, acquisition of HA domains that fool the human immune system, either by mutation or recombination, make viruses more effective in infecting us, and figuring out how those changes came about may help us understand the causes and likelihood of future outbreaks.

In "Questioning the Evidence for Genetic Recombination in the 1918 "Spanish Flu" Virus", Worobey et al., conclude that, "Phylogenetic analysis of [HA] gene sequences has indicated that the [1918 strain] was more closely related to the human lineage than to the swine or avian influenza lineages of the H1N1 subtype", and that, "The apparent recombination...results from difference in the rate of evolution between HA1 and HA2 -- a difference present only in human influenza A viruses".  The group who published the tree supporting porcine origin, or more specifically, recombination between human and porcine flu strains, maintains their position in a response published with Worobey et al.

Finally, Reid et al. analyzed both the HA gene and the neuraminidase gene (NA) from the 1918 strain, concluding that its HA and NA genes were avian in nature, and that the virus had been been adapting within a mammalian host for at least several years preceding 1918.  They also note that pigs evidently came down with the same flu in the fall of 1918, which seems to indicate pigs got it from us, not the other way around.

I can't say that any of this helps me sort out whether current conditions in SE Asia mean we are particularly at risk of pandemic strain of Avian Flu emerging soon.  If nothing else, it is clear that we need to put more effort into understanding the evolution of RNA viruses, in particular.  And precisely because it is unclear whether the 1918 strain emerged due to mutation -- perhaps aided by the use of mutagenic chemical weapons on the battlefields of France -- or just plain old recombination, we need to do whatever is possible to reduce the chance of other diseases, such as malaria, producing conditions conducive to the spread of flu bugs in Asia.


First a few words worth of primer on terms.  Mutation is an alteration of nucleic acid sequences, caused by mistakes in enzymatic copying, ionizing radiation, or chemicals, within the genome of an individual member of a species.  Recombination is an exchange of genetic material between individuals of the same species.  For example, Strain A and Strain B of a virus may coincidentally infect the same cell, thereby creating the opportunity for their genes to mix, resulting in Strain C, which combines features of the two.  Reassortment is an exchange of genetic material across species.  Flu viruses can pick up human or avian sequences, and vice versa.  An interesting variant of the latter is the fact that mammals seem to employ a protein derived from an endogenous retrovirus in generating the placenta.  This is a fairly recent story, exemplified by this paper,"Syncytin-A and syncytin-B, two fusogenic placenta-specific murine envelope genes of retroviral origin conserved in Muridae".

Clarification (3 March 2005):  Or perhaps further confusion. The usage of "reassortment" and "recombination" is a bit inconsistent in the virology literature.  It may be that virologists know exactly what they are talking about, but it isn't clear from reading academic papers, or news stories, that everyone is using those words the same way.  This is important, because we may not all be talking about the same mechanisms of genetic alteration.  In "The evolution of bovine viral diarrhea: a review," by Denise Goens (Can Vet J. 2002 December; 43(12): 946-954) we find exactly the opposite of the definition I gave above;

Reassortment occurs only in RNA viruses with segmented genomes (such as influenza viruses) and refers to the regrouping of genome segments with segments of other isolates, species, or genera of RNA viruses...Recombination can occur between host and virus, resulting in host RNA sequences being inserted into the viral genome or by rearrangement, duplication, or both of the viral genome's nucleotide sequence.

I stumbled over this only after a fair bit of Googling.  Ah, the magic of the web.  (Who ever thought a PhD in physics might lead to reading papers about bovine diarrhea?)  I still am not sure which definition is correct.