First human infections with avian influenza H7N9 virus

4 April 2013

comingled birdsFourteen people in China have been infected with avian influenza H7N9 virus, leading to five deaths. This avian influenza virus has never been isolated from humans.

Influenza A viruses with the H7 hemagglutinin protein circulate among birds, and some, such as H7N2, H7N3, and H7N7, have been previously found to infect humans. It is not known how the individuals in China acquired the H7N9 virus. Some of the infections have occurred in Shanghai, where a similar virus was found in pigeon samples collected at a marketplace in that city. It is not clear what types of pigeon samples tested positive for the virus, nor is it known whether the virus spread from poultry to pigeons or vice versa. In response the city has begun mass slaughter of poultry to stem further spread of the virus.

Influenza H7N9 virus is typically a low-pathogenicity virus, which means that infection of chickens causes mild respiratory disease, depression, and decrease in egg production. The virus does not have a basic peptide between HA1 and HA2. The presence of a basic peptide in this location allows the viral hemagglutinin glycoprotein to be cleaved by proteases that are present in most cells, enabling the virus to replicate in many organs. Without this basic peptide, the HA is cleaved only by proteases present in the respiratory tract, limiting replication to that site.

According to Brian Kimble on Google+, the nucleotide sequence reveals that the H7N9 human isolate is a reassortant* with 6 RNA segments encoding the internal proteins PB1, PB2, PA, NP, M, and NS derived from H9N2 virus, and the HA and NA from H7N9 virus. The significance of this observation is not clear, because I do not know if H7N9 viruses isolated from birds are also reassortants. One possibility is that reassortment produced a virus that can infect humans. It is known that reassortants of H9N2 viruses with the 2009 pandemic H1N1 strain can transmit via aerosols in ferrets.

An important question is whether this H7N9 virus isolated from humans has pandemic potential. So far there is no evidence for human to human transmission of the virus. There is no vaccine for this subtype of influenza virus, but the virus is susceptible to neuraminidase inhibitors oseltamivir and zanamivir. WHO has released the following statement:

Any animal influenza virus that develops the ability to infect people is a theoretical risk to cause a pandemic. However, whether the influenza A(H7N9) virus could actually cause a pandemic is unknown. Other animal influenza viruses that have been found to occasionally infect people have not gone on to cause a pandemic.

*Because the influenza virus genome occurs as 8 segments of RNA, when multiple viruses infect a single cell, new viruses can be produced with combinations of the parental segments, a process known as reassortment.

Update: Peter Palese notes that the human H7N9 isolates do not have a serine in position 61 (as does the 1918 virus). This change is a human virulence marker for some animal influenza viruses. Brian Kimble notes that the H7N9 isolates possess a L226 equivalent in the HA, which confers human-like receptor binding in other viruses. Human influenza viruses prefer to bind to alpha-2,6 sialic acid receptors, while avian strains bind alpha-2,3 sialic acids. If the human H7N9 viruses can bind alpha-2,6 sialic acid receptors then they are adapted to infect the human upper respiratory tract.

  • Junio C Hamano

    Sorry for not commenting on virology in advance.

    “… infection of chickens causes mild respiratory disease, depression, and decrease in egg production.” sounded funny to a layperson like me. Ornithologists can diagnose “depression” in birds?

    For the external link to your post where Brian gave comment on G+, it is better to use

    https://plus.google.com/116255230904882614629/posts/1tkxujwnkLs

    as the link. To find this link, go to the circle-down-triangle at the right-top corner of your post, and pick “Link to Post”.

    The version that you used, which ends with “…/posts”, will lead the readers to the list of posts made by you (which will change as you post new messages, like the next TWiV announcement).

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  • Kathryn Marks

    Wonder if there will be sneezing ferrets involved. Does the H5N1 restriction will be extended to this new re-assortment.

  • gsgs

    The 6 internal segments are common in chicken-H9N2 circulating since > 10 years

    Rare HA7 and NA9 are now newly introduced probably from wild birds
    and presumably

    ~1 year ago. This is a more dramatic change in the virus than the usual
    reassortments

    between similar H9N2s. Subsequent reassortments (at least 1, probably 3
    IMO)

    with established poultry H9N2 did also happen. Most notably 2 of the
    viruses have

    different NP-segments with a most recent common anchester ~5years
    ago.

    But probably there was a further reassortment just some months ago giving
    them

    segments 3,7,8 which are now more similar than the others (1 year old) now.

    (this is my interpretation)
    I think this shows that the virus did probably not
    evolve in mammals

    for prolonged time as suggested elsewhere.

  • http://www.virology.ws profvrr

    No, this is a low pathogenicity virus so it will not be subjecte to the same restriction.

  • http://www.virology.ws profvrr

    Thanks for the information.

  • http://www.virology.ws profvrr

    Thanks for the correction on the link. I must say that Google+ is really not transparent in many ways. It always takes me a long time to find things and I’m not new at this.

    As for ‘depression’, I don’t believe it’s psychological depression, but behavioral. Here is the full description from a textbook: “Based on their pathogenicity in chickens, avian influenza viruses are classified as highly pathogenic avian influenza (HPAI) or low pathogenicity avian influenza (LPAI) viruses. LPAI viruses cause mild respiratory disease, depression, and/or a decrease in egg production. For outbreak control purposes, the Office International des Epizooties (OIE) classifies an avian influenza virus as HPAI if it is “lethal for six, seven, or eight
    of eight 4- to 8-week-old susceptible chickens within 10 days following intravenous inoculation with 0.2 ml of a 1/10 dilution of a bacteria-free, infective allantoic fluid” (OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals 2010; accessible at: http://www.oie.int/en/international-standard-
    setting/terrestrial-manual/access-online/), or if it has an intravenous pathogenicity index (IVPI) greater than 1.2 (the IVPI is the mean clinical score of ten 6-week-old chickens intravenously infected). All H5 and H7 viruses of low pathogenicity in chickens with a multibasic sequence at the HA cleavage site
    are considered highly pathogenic.

  • http://www.virology.ws profvrr

    Do you know whether H7N9 viruses circulating in birds are also reassortants with H9N2?

  • Alan Dove

    You can tell a chicken is depressed because it’s feeling down.

    Sorry, couldn’t resist.

  • gsgs

    H9N2 is very successful in Asean poultry, there are several different
    variants.

    But flu usually doesn’t spread back from poultry to wild birds (i.e.
    mallards), so the known

    wild H7N9 reassortants are distant and thus unclear.

    I get ~20 (out of ~5000) wild bird H7N9 viruses at genbank.

    HAs and NAs switch frequently in wild birds and H9N2 is also in wild
    birds

    ,but non-poultry-variants, so H7N9+H9N2 reassortments may well happen in
    wild

    birds. But It clearly seems that this new H7N9 reassortment happened in
    poultry, probably chickens.

  • gsgs

    LPAI sometimes (~30%?) converts to HPAI after months or years of evolution in chickens. That’s why they cull even with LP. So there is room for further increase of virulence in humans …

  • http://www.facebook.com/jianping.hua.1 Jianping Hua

    If the human H7N9 viruses can bind alpha-2,3 sialic acid receptors then
    they are adapted to infect the human upper respiratory tract.

    Could not understand this last sentence.

  • gsgs

    Palese meant N66S in PB1-F2 ? But poultry H9N2 also has 66N

    Jinping Hua, 2,3 could be another typo meaning 2,6

    chickens have 2,3 – Pigeons and mammals have mainly alpha 2,6 – Quail have
    both

  • Junio C Hamano

    Does that mean finding samples in pigeons is more significant than finding them in chickens from public health perspective?

  • http://www.facebook.com/jianping.hua.1 Jianping Hua

    If it’s a typo, then it makes all the sense to me now. Thanks.

  • gsgs

    I speculate pigeons or quail could be responsible for the mammalean
    markers,

    but I don’t really know, a discussion about this would be interesting.

    you can search pubmed for papers

    http://www.ncbi.nlm.nih.gov/pubmed/?term=influenza+quail+h9n2

    http://www.ncbi.nlm.nih.gov/pubmed/22416344

    http://www.ncbi.nlm.nih.gov/pubmed/20347894

  • Jody Lanard M.D.

    Why would there be a distinction in research rules for a LPAI flu causing severe disease in humans versus a HPAI flu causing severe disease in humans?

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