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High Human Avian H7N2 Reassortant Levels in Ferret Noses

Recombinomics Commentary 03:11
April 29, 2008

an lung viral titers of NY/107 were at least 10-fold higher than those of all other H7N2 viruses on day 3 p.i. and were significantly higher on day 6 p.i. (P < 0.03)

Both H7N7 viruses examined replicated to high titers in the nasal turbinates and lungs. NY/107 virus, but not Tky/VA virus, was found at a similarly high titer in the nasal turbinates.

It is noteworthy that despite the lack of substantial morbidity or mortality observed following infection of mice and ferrets with the North American viruses examined in this study, we observed efficient infection and replication within the respiratory tract in both animal models. Virus titers measured in the respiratory tract of ferrets were even higher than those observed following infection with human H3N2 viruses (40, 53). The isolation of NY/107 virus from tissues of the olfactory bulb of ferrets could be due to the proximity of the high virus titer attained in the nasal turbinates following i.n. inoculation with this virus and may not be an indicator of extrapulmonary spread, as a similar pattern of replication was also demonstrated with ferrets infected with a human H3N2 virus (53).

The above comments are from the paper, “Pathogenesis of Avian Influenza (H7) Virus Infection in Mice and Ferrets: Enhanced Virulence of Eurasian H7N7 Viruses Isolated from Humans,” which includes the isolate, A/New York/107/2003(H7N2), which is a reassortant with human flu genes (PB1, PA, MP, NS).  The above comments describe the ability of the virus to cause respiratory disease and grow at high levels in ferret nasal passages, which were at levels higher than H3N2 seasonal flu.  These data increase concerns that the virus can be efficiently transmitted human to human.

These properties may be enhanced by E627K in PB2.  The PB2 sequence has not been released, but since the H7N2 virus has two human polymerases (PB1 and PA), it is likely that PB2 is also human, which would strongly suggest that the virus has E627K, which is in all human seasonal flu.  E627K allows the virus to replicate more efficiently at lower temperatures, such as those found in a mammalian nose.

However, the paper, which was submitted in June, 2007 makes no mention of the fact that the avian isolates is a reassortant with 4 or 5 human genes, including at least two polymerase genes.  The HA sequence was already known, because the isolate is in a phylogenetic tree in the paper, but it is curious that the PB2 E627K status isn’t mentioned, since it was discussed in relationship to the human H7N7 sequence from the fatal infection of a veterinarian, and its association with increase virulence in mice, which was the other model used in the paper.

The sequences were deposited at Genbank on March 24, 2008, so the timing of the sequencing remains unclear.  However, since this is the first example of a human / avian reassortant in H7, it seems that it would have been mentioned in the above paper.

In any event, the presence of four or five human H3N2 genes in avian isolates is cause for concern.  Detecting H7 in humans has been a challenge, so there may be more such reassortants in circulation in humans and birds.  This circulation could lead to more interspecies interactions leading to additional exchanges of genetic information.  The H5N1 PB2 in the vaccine resistant strain in Israel has a number of newly acquired human polymorphisms and HA has M230I encoded by sequences found in H5N1 as well as H7 isolates, which was reported in Egypt.

H7 has also been recently reported in North and South Korea, which may be related to Korea’s proximity to North America.  H5N1 has been repeatedly detected in South Korea and Japan, including isolates linked to wild birds.

It is becoming increasingly clear that wild birds have an extensive distribution network which shuffles genes via reassortment and gene segment via recombination, creating increasing genetic diversity which will challenge vaccine efforts.  Japan has announce a pre-pandemic plan and the US has recently order 38.5 million doses of vaccine directed against clade 2.2 (Qinghai strain), which is becoming increasingly widespread and likely cause a human infection of a soldier in South Korea.

The sequence of the H7N2 PB2 as well as reasons for the 4 ½ year delay in the release of the sequences from the reassortant would be useful.

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