Tuesday, 19 February 2008

The bioinformatics of the 'flu

What was the most lethal epidemic of infectious disease in modern times? AIDS perhaps? You might think so, but you would be wrong. Between the beginning of the epidemic and the end of 2007, AIDS killed people 25 million; the influenza epidemic of 1918 killed 40 million. This vast figure is also about double the number who died in the First World War, which ended the same year. Furthermore, a high proportion of those deaths were of healthy individuals in the prime of life. Yet most of the time we think of influenza as little more than a very nasty nuisance...

However, there has recently been a renewed interest in past influenza epidemics as a result of the result of the virulent strain of influenza currently sweeping through populations of wild and domestic birds worldwide. The influenza virus is endemic in birds, and strains tend to spread periodically from them to mammalian hosts: pigs as well as humans. Mapping genetic changes in the influenza virus, and how these affect its spread, is an important research area. Richard Goldstein of the National Institute for Medical Research, based in Mill Hill, London, gave a fascinating Monday seminar on this topic yesterday, looking into the past to see how genetic changes could have led to the lethal 1918 epidemic.

Influenza viruses contain two proteins on their spherical surfaces: a neuraminidase and a hemagglutinin. These proteins come in various forms: 16 different hemagglutinins are known, and 9 different neuraminidases. Any influenza virus can be characterised by these variants - for example, the most common type of influenza currently afflicting humans is H3N2, and the feared bird flu H5N1. Recent flu epidemics appear to have been caused by reassortment events, where the genomes of different viral subtypes combine to form an entirely new one that will not be recognised by human immune systems. An epidemic in 1957, for instance, coincided with a shift from influenza H1N1 (which had been circulating since 1918) to H2N2.

Influenza virus hemagglutinin and neuraminidase are both mainly-beta proteins, and their structures are described further on this page of PPS section 5.

So, what happened in, or before, 1918 to cause the epidemic of H1N1 flu? Molecular geneticists, such as Goldstein, study this by reconstructing phylogenetic trees showing the evolutionary distance between viral isolates taken in different places at different times. Yet most of these calculations can only show evolutionary distance, not the direction of change - in the jargon of phylogeny, they produce unrooted, rather than rooted, trees (there is no known "top"). The research was at rather an impasse until postdoc Mario dos Reis (a Birkbeck Ph.D.) noticed that the GC content of viruses infecting humans, but not of those infecting birds, decreased over time. This enabled the group to add an evolutionary "clock" to the phylogenetic tree for each of the influenza virus' 11 genes. This showed that some of the genes had entered the human population at different times, indicating that the variant that caused the 1918 flu had arisen from several recombination events. Interestingly, only one gene (neither H nor N) could have made the jump in 1918; most viral proteins were present in the human population in their 1918 forms well before that year. M1, like some other proteins, appears to have made the shift in 1899.

So, what did happen in 1918? There do appear to have been changes to the H gene then. But it may also be possible that the world population was so debilitated, and susceptible, after four years of war that a variant that had already been around for a few years was, unusually, able to cause such an epidemic...


Nicholas said...

Very Interesting Blogs Clare. It's nice to put our studies into a practical context. I assume members of PPS07 are permitted to attend seminars. With this assumption in mind could we be directed to a page (or sent an email) with dates, times, locations, speaker and intended subject matter? I probably will not attend many (due to work comittments) but I am sure I could make one's I and my boss seem relevant.

Philippe said...

Hello Clare and all of you following this blog,

This seminar is an excellent opportunity to discuss about flu. Actually the team I work in at EMBL focuses on proteins from this virus. I will try to give you a quick overview of our recent results, without drowning you in too much details. Our team succeeded, thanks to ESPRIT technology, to get a structure of a piece of one of the three sub units of the influenza polymerase (RNA dependent RNA polymerase). This structure was performed by MNR.

But why is it so important to focus on the polymerase? This RNA polymerase is not only involved in the steps of the RNA viral replication, but also leads the build up of the viral protein from the host cell. So, no matter of the serotype (from Hemagglutinin or Neuraminidase), the polymerase is common to all influenza species.
The polymerase is made of three subunits: (PB2, PB1, and PA)

What the structure taught us from influenza polymerase? This identification of the Cterminal part of subunit PB2 allows determining a bipartite signal of nuclear localization signal. Importin alpha 5, a cargo protein required to integrate proteins to the nucleus, recognize this signal and lead the polymerase to the nucleus. It has been demonstrated also that mutations on the polymerase might be responsible of crossing species between bird viruses to mammalian ones. The analysis of the structure, and also in vivo experiments has shown that these mutations were located near the interaction site of the Importin AND the polymerase. This suggests that mutations might affect the nucleus transport efficiency, and hence the virus capacity to propagate in different species.

For further details if you are interested in, I advise you to read the following paper:
Franck Tarendeau, Julien Boudet, Delphine Guilligay, Philippe Mas, Catherine M Bougault, Sebastien Boulo, Florence Baudin, Rob W H Ruigrok, Nathalie Daigle, Jan Ellenberg, Stephen Cusack, Jean-Pierre Simorre & Darren J Hart (2007).
Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit.
Nature Structural and Molecular biology, 14(3):229-33.