Evolution of the Flu Virus

i-96914fa457dda10e92990f0d4ed3fc49-flu_pandemic.jpgThe flu is caused by the influenza virus, of which there are several types. H1N1 is known as the "Spanish Flu," H2N2 as the "Asian Flu" and so on. These funny letters and numbers refer to specific genotypes. The H1N1 is the version of the flu that caused the Great Influenza Pandemic of 1918 and 1919, which was responsible for the death of between 50 and 100 million people.

Considering that the difference between a bird or pig flu that may be hanging around in the background and a human pandemic causing flu can be a few dozen changes in the genome, understanding the evolutionary patterns for Influenza A viruses seems important.

ResearchBlogging.orgViruses do not really have chromosomes, but their genome does have sections that tend to stick together and that can be reassorted across strains. If an individual is infected with two strains of a certain virus, you can end up with a novel virus by this reassortment. The genetics of the new virus could be sufficiently different than that of either "parent" to cause a different relationship between the virus and potential hosts. This could be how a virus can show up in a species seemingly out of nowhere. Such a novelty could seriously challenge the immune systems of individuals in the new host, and result in the spread of a virulent strain.

This appears to have happened. New research published in PLoS Pathgens suggests that the H1N1 strain of influenza had done this.

...two of these reassortment events appear to be associated with particularly severe epidemics, those of 1947 and 1951. Our analysis reveals that the virus associated with the 1947 epidemic was composed of genome segments with differing phylogenetic histories, suggesting that this virus was created through an intra-subtype reassortment event.

In addition, a virus likely associated with the 1951 epidemic also appears to have been generated by a reassortment event. Overall, our findings suggest that reassortment is an important factor in the long-term evolution of influenza A virus, including the periodic emergence of epidemic viruses. However, to more fully capture the evolutionary history of this important virus, additional sequencing of influenza viruses from earlier time periods is clearly needed.

If we assume that viruses evolve base pair by base pair, then we would arrive at a fairly straightforward set of expectations that are testable with genetic data from samples preserved from various epidemics. (I should mention that there are sample going back quite far because, for one, the US Military traditionally keeps tissue samples related to disease treated in its facilities ... there is a library of tissue samples going back to the mid 19th century.)

Imagine in this simple model (which we might call "microevolutionary" ... though don't put too much weight on that term, please) that there is a swine or bird virus is unable to infect humans ... because the virus can't us a certain cell-surface receptor site in humans, but manages it in it's normal host. Then, through a series of chance mutations, a minor variant of this virus emerges that can infect humans. But, most of the time it does not happen to make the jump. But, one day a sick swine sneezes on a hapless farm boy, the virus makes the jump, he goes to school and sneezes on his teacher, and so on, and the next thing you know there is a pandemic.

If that happened, it would be possible to see a straightforward transition from the swine flu passing around at the time and the human flu that emerges.

However, it is notable that putting this story together has been difficult for flu researchers. There are epidemics that show early cases, say, in the swine industry but no solid link between a swine virus and the human virus showing just a few changes in the genome. The situation often seems much more complex, and it has been the case that particular scenarios have been dismissed as a coincidence.

However, if the transition involves a wholesale reassortment of a large portion of the genome, a transit form bird or swine to human may occur but not be identifiable with the "micromutation" model. In a sense, the reassortment model is like a "hopeful monster" in the sense that a large number of changes happen in a single evolutionary event.

The fact that many definitions of "life" would exclude viruses, and that they act very differently than, say, horses or amoebas reproductively makes the term "hopeful monster" a bit dicey in this context, but you get my point.

Let's go back to the study for an example.

The most notable observation from our study is that [one particular] reassortment event appears to coincide with the unusually severe post-World War II influenza epidemic of 1947, which caused a total influenza vaccine failure worldwide although with relatively low mortality [7]. Previous analyses revealed that the HA1 region of the hemagglutinin of these 1947 epidemic influenza isolates ... were highly divergent from those of the less virulent isolates sampled between 1943-1945, ... Based on this marked antigenic change, Kilbourne et al. ... suggested that the 1947 epidemic viruses did not evolve directly from the 1943-1945 viruses that were dominant earlier, but rather may have been derived from a minor A/H1N1 clade that was circulating undetected. In our analysis, [this] epidemic virus is closely related to clade D viruses in each of the eight segments ...and therefore follows the exact same evolutionary pattern as the reassortant clade D. Thus, this phylogenetic analysis suggests that the 1947 epidemic virus was generated by a major reassortment event...

Our analysis also suggests, more tentatively, that the virus responsible for the unusually severe 1951 epidemic in some geographic regions may have been generated by a genomic reassortment event. ... The extensive evolutionary change in six of the eight viral gene segments generated in this reassortment event may resolve the quandary over how a virus that displayed little antigenic drift in HA caused such a severe epidemic .... It has been previously suggested that the severity of the 1951 epidemic in the UK and Canada was related to the high transmissibility of the virus circulating in these countries, which perhaps resulted from enhanced viral replication within hosts ... Our finding that [this virus retained some genes but acquired others en masse] through reassortment suggests that these viruses indeed may have been antigenically similar but replicated with enhanced efficiency. ...

The ultimate significance of this research is unknown, but this appears to be the first time that major evolutionary events in viral history ... linked to major public health events ... can be explained best by reassortment rather than other patterns of genetic change.

Nelson, M.I., Viboud, C., Simonsen, L., Bennett, R.T., Griesemer, S.B., St. George, K., Taylor, J., Spiro, D.J., Sengamalay, N.A., Ghedin, E., Taubenberger, J.K., Holmes, E.C., Kawaoka, Y. (2008). Multiple Reassortment Events in the Evolutionary History of H1N1 Influenza A Virus Since 1918. PLoS Pathogens, 4(2), e1000012. DOI: 10.1371/journal.ppat.1000012

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I wonder why is it the "bird" flu and not the "mammal" flu, that is why are so many of species of birds susceptible to a given virus while the human and porcine varieties do not infect many other type of mammals?


The following answer is based on how I think this works having read quite about about influenza but not being a certified expert. So I'm pretty sure this is correct.

Influenza is basically a water born virus that lives part of its life cycle in the body of birds (typically water birds). But this statement is as true as saying that primates are tropical animals that mainly eat fruit and insects. There are plenty of primates that eat mostly leaves, and a few that live well outside the tropics.

So the general pattern is broken by some influenza strains that do just fine in various mammals, probably circulating among those mammal populations now and then, but it is probably only very widespread, fairly dense, and frequently interacting mammals that you find influenza at any frequency: Humans and livestock for instance.

In the mean time, influenza can pass between species. One would think that it would pass more easily between closely related species and with more difficulty between distantly related species. This may be true in the very large picture (averaging over many instances) but I think most virus experts feel that influenza is largely "indifferent" in this way. Rather, there is variation among vertebrates (chordates? Tetrapods? some larger phylogenetic group) because all it really needs is the correct receptor site on a cell, and from the point of view of a virus of a particular strain, there is a small number of different receptor sites (of which a couple/few would work).

So one bird virus may mutate to also be able to grow in a pig, another sub population of the same virus to grow in a human but not a pig.

Greg, very, very interesting post! I am actually reading some stuff on biology and genetics currently (out of interest) so this post and the article came at about the right time.

I still need to grasp some concepts better though :-)


Thanks for the reply, I would have followed up quicker but I have been down with the very virus we are discussing here. You explanation really helps, but I am still confused about why so many species of birds are susceptible. In particular when they talk about transmission from wild birds to domestic birds. I could understand duck to duck transmission but then the jump to something like chickens or turkeys seems a bit odd. Even more confusing, I also had the feeling the actual carries were smaller birds like sparrows and the like which are not waterfowl.

So, I guess my question is why are so many types of birds susceptible to the same virus when movement between species in mammals is such a rare event in comparison?

A big part of this is me also trying to sort out what are the real facts, issues, and mechanisms in this area and what are misperceptions I have picked up from way things are simplified in the popular media. Thanks for your help!