Thursday, April 18, 2013

New paper suggests H7N9 has high rate of mutation

Jonges M, Meijer A, Fouchier RA, Koch G, Li J, Pan JC, Chen H, Shu YL, Koopmans MP. Guiding outbreak management by the use of influenza A(H7Nx) virus sequence analysis. Euro Surveill. 2013;18(16):pii=20460. Available online:  
Also had high mutation rates

The author compare the genetics of isolates from 3 H7 outbreaks fromt he last 15 years: 2003 Netherlands outbreak of high path H7N7, 99/00 low path H7N1 in Italy, and the current Chinese H7N9 outbreak. They note that all four of the Chinese isolates have the E627K humanization marker in the PB1, but no bird or environmental sample does. They give two possible explanations for this:

"1. the mammalian adaptation markers are selected during replication in humans following exposure to viruses that do not have this mutation, which are circulating in animals;
2. the mammalian adaptation markers result from virus replication in animals from which humans become infected.
The relatively protracted disease course in the current outbreak of A(H7N9) virus infection, with relatively mild symptoms at first, followed by exacerbation in the course of a week or longer, is suggestive of the first hypothesis, similar to the outbreak in the Netherlands."
Comparing the human markers in viruses from the NL outbreak and this one shows some discrepancies. Namely, 1/61 human H7N7 cases had the 627 mutation, while 4/4 H7N9 did (no bird or environmental isolate in the current outbreak carries the mutation).  They go on to conclude that this is due to a higher mutation rate in the Chinese viruses based on the comparison of the maximum genetic distance of isolates from different outbreaks of H7s.

"The maximum genetic distance generated during the three months of the Dutch HPAI A(H7N7) outbreak in concatenated HA, NA and PB2 segments of A(H7N7) viruses was 25 nucleotide substitutions. For the Italian LPAI A(H7N1) epidemic, the distance generated during a nine-month period was 66 nucleotide substitutions. For the A(H7N9) outbreak strains, this genetic distance is 35 substitutions"

New mutations arise randomly. However, the rate of mutations is relatively constant over time given equal rates of replication (the number of infections). Over three months and hundreds of samples the most genetically dissimilar isolates from the Netherlands outbreak were 25 nucleotides. The Italian outbreak lasted three times a long and the genetic diversity was slightly less than three times greater.  The Chinese H7N9 shows a roughly equal amount of mutations as the NL outbreak in 1/6th the time over presumably far fewer infections. The caveat here is that we are looking at only 7 H7N9 samples. As we get more and more data on these viruses we may see less diversity... or we may see more.
Those two points combine point to a non-humanized virus transmitting into humans from birds and then picking up humanization markers as the replicate. It could very well be the case as (at least the first three) isolates show a lot of genetic differences.  Depending on high mutation rates and still ending up with the same markers is surprising and indicates that these markers are not just "A" way the virus becomes humanized, but "THE" way it happens. Additionally, all the isolates recovered so far show a deletion in the NA stalk that is a hallmark of replication in chickens and other gallinaceous birds. This suggests that the virus spent time in these birds and became adapted and then transmitted to humans from there.
Common galliforms: Turkey, chicken, pheasant, guinea fowl, quail, etc.
One other option that they did not discuss is sub-populations. Flu as an RNA virus exists as a quasi-species. The birds could be carrying a version of the virus with some human markers at very low levels that are undetectable with standard sequencing methods (I don't think deep sequencing, limiting dilutions, or plaque isolations have been done yet). These minority populations could be the ones that transmit to humans. I would still lean towards their model based on the evidence available, but its something to think about.
So far the sequencing has not revealed any H2H transmission. If the model they propose in the paper is correct, then this is surprising. If the viruses are mutating at such a high rate, still arriving at the same set of mutations independently and showing no H2H transmission, then maybe there is no set of mutations that will allow it (maybe that is why there has not been an H7 pandemic before). This would also raise the question of why is the virus mutating so much faster.

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