arginine from Wikicommons
New biological route for swine flu to human infections
[Via EurekAlert! - Infectious and Emerging Diseases]
A new biological pathway by which the H1N1 flu virus can make the jump from swine to humans has been discovered by researchers with the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California, Berkeley. Early test results indicate that a heretofore unknown mutation in one of the H1N1 genes may have played an important role in transmitting the virus into humans.
“Transmission of influenza viruses into the human population requires surmounting biological barriers to cross-species infection,” says biochemist Jennifer Doudna, the principal investigator for this research. “We have identified an adaptive mutation in the swine origin H1N1 influenza A virus – a pair of amino acid variants termed the ‘SR polymorphism’ – that enhance replication, and potentially pathogenesis of the virus in humans.”
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Understanding how the influenza virus replicates in both swine and human cells is an important goal. In this research (which is Open Access), they have identified some amino acid changes in the viral polymerase that allow H1N1 to rapidly replicate. In this case it is an unexpected amino acid change that had not been seen before:
The influenza polymerase consists of three proteins dubbed PB1, PB2 and PA, that work with viral RNA and nucleoprotein to transcribe and replicate the influenza genome in a host cell. Earlier work by Doudna and Mehle with avian influenza had shown that a mutation in the viral protein PB2 – whereby glutamic acid is replaced at a certain position on the amino acid chain with lysine – enables the virus to jump from birds to humans. When glutamic acid is retained in PB2, its presence suppresses the polymerase from performing in human cells.
H1N1 contains the suppressing glutamic acid residue in the protein. So how does it replicate so well in humans? It turns out there are other amino acid alterations. In this figure from the paper, the previously important residue 267 is shown. Previous swine flu versions (pre-2009) that infected humans had a lysine (K) here instead of the glutamic acid (E) found in avian flu. It used to be that if the glutamic acid residue was there, replication could not really happen in humans. This is one reason that avian influenza is not very infectious in humans. It can not replicate.
That is what is a little scary about the new 2009 H1N1 virus. One hundred percent of all the new isolates have the glutamic acid residues that should prevent replication in humans. But it replicates fine. Turns out it is due to the other change. Every other influenza virus looked at generally contains a glycine (G) and glutamine (Q) around residue 590. The 2009 H1N1 has two different amino acids here – a serine (S) and an arginine (R). The R change had only previously been seen together in 3 out of almost 3,000 isolates before 2009. Yet now virtually 100% of the H1N1 swine flu isolates have the SR changes.
Modeling the changes on the structure of the polymerase reveal that the arginine at 591 could interact with the glutamic acid at 627. So this may indicate that the SR change reduces the negative effects of the 627 residue , allowing replication to occur in humans. The group did a series of experiments mutating the different residues to see what happened in human cells.The K267E mutation was the best. If the 267E wild type is left, then there is only good replication with the 590 SR changes. If the SR changes are included with the K267E mutation, there was no enhancement.
This they conclude that the SR change acts to reduce the negative effects of the 267E residue for replication in human cells. Then they did something very neat. Avian influenzas, so-called H5N1 viruses, have the ‘bad’ 267E residue indicating that they can not replicate well in humans. Good for us and a possible explanation for their low infectivity.
When they add the SR changes to wild type avian flu, the polymerase activity goes up 26-fold in human cells. This is much less than seen if only the K267E mutation is there but it something to notice.
In the past, surveillance approaches would look for things like the K267E mutation as a signpost towards greater virulence in humans. This work shows that some important strains would be missed by this approach. Now we know to include the SR duo.
Sure am glad we have better tools today to examine this sort of thing. We may need to use them a lot, unfortunately.
