Avian Influenza A H7N9 emerging human cases around Shanghai, China

GISAID data acknowledgements

We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GISAID’s EpiFlu™ Database on which this analysis is based. A list of the sequences, their submitting labs and GISAID links is provided on this page.

Clinical case study of the first 3 cases

The Chinese CDC have published a paper in the New England Journal of Medicine describing the first 3 cases including phylogenetic analysis:

http://www.nejm.org/doi/full/10.1056/NEJMoa1304459

Analysis and interpretation

The main findings of the phylogenetic analysis is that although the human cases are a H7N9 virus, this seems to be an independent reassortment of 3 avian viruses: the HA (H7) from a H7N3 virus, the NA (N9) from a H7N9 virus and the remaining segments from a number of H9N2 virus. Thus, interestingly, this is a new bringing together of H7 and N9 that we haven't observed in birds. Given the high frequency of reassortment in wild birds it is quite possible that it simply hadn't been sampled.


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Did everybody notice that the 3 more complete sequences of the novel influenza A/H7N9 virus released in GISAID, one from chicken, one from pigeon and one from an environmental sample from a live bird market, all 3 new PB2 sequences from birds and the bird market have 627E (while the human samples have 627K), likely indicating  that the virus likely revert to PB2 627K during replication/selection in people?

Indeed, very interesting. In PB2 the pigeon and chicken sequences group together but that could represent an independent reversion of K627E (given the more basal A/Shanghai/1/2013 is K). That might suggest that these represent spill-over infections of birds from the outbreak reservoir. Or they could represent the reservoir and there have been multiple E627K mutations in each human jump.

Of course difficult to say for sure, but I think that grouping together is based on very few differneces/changes and at this point, I think it is more likely that the change happened during human infection, in particular considering that the isolates from human samples likely are isolated fairly late in the infection giving plenty of time for selection. I believe that experiments done by FLI  with infection of mice with a cloned virus with a similar change in PB2 in a H5N1 background reverted in 3 days or so in mice but not in chickens. Anyway, it is too early to say for sure.

I agree that the only reason the 3 bird viruses group together in this segment is because of this one shared change. I also agree that it is quite possible that each of the 3 human cases independently gained this mutation during the course of their infection (the date of sample collection is between 2 and 3 weeks after the likely date of infection). What this probably means is that this is not an important mutation in making this virus more susceptable for humans but rather a minor adaptation once the jump has been made.

It's interesting to note that almost all H5N1 viruses in clade 2.2.1 and the subclades contain PB2 with this mutation. The evidence for a role this mutation may have in adaptation, pathogenicity and transmission risk in naturally occuring viruses is not clear. 

The studies by FLI on H5N1 suggest that this change is selected for in mammals (they used mice) and while it is not selected for/changed in poultry it does not flip back when first made and then put back into chickens. Consequently, depending on the NP (which is also important for this), it appears to be important/essential in mammals but without much consequence whether present or not in poultry and consequently, only specifically selected for in mammals and not in poultry.

Interesting then that the new A/Zhejiang/DTID-ZJU01/2013 isolate doesn't have 627K (it has E). It suggests to me that each of these E267K mutations are occuring de novo in the human host that the virus is isolated from. Given the first 3 cases all have a relatively long time between onset and sample collection, this doesn't seem implausible.

I agree that it is most plausible that it happens when selected for during a period of replication in the mammalian host, my point of argument from the beginnig.

Jesse Bloom's picture

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