Effect Measure

The headline was worrisome: “Bird flu becoming riskier for humans.” The story was about a new paper in PLoS Pathogens from Kawaoka’s lab that was said to identify “a specific change that could make bird flu grow in the upper respiratory tract of humans,” according to the lab leader.

Birds usually have a body temperature of 41 degrees Celsius, and humans are 37 degrees Celsius. The human nose and throat, where flu viruses usually enter, is usually around 33 degrees Celsius.

“So usually the bird flu doesn’t grow well in the nose or throat of humans,” Kawaoka said. This particular mutation allows H5N1 to live well in the cooler temperatures of the human upper respiratory tract.

H5N1 caused its first mass die-off among wild waterfowl in 2005 at Qinghai Lake in central China, where hundreds of thousands of migratory birds congregate.

That strain of the virus was carried across Asia to Africa and Europe by migrating birds. Its descendants carry the mutation, Kawaoka said.

“So the viruses circulating in Europe and Africa, they all have this mutation. So they are the ones that are closer to human-like flu,” Kawaoka said. (Australia Associated Press)

This is pretty scary sounding but it isn’t new scary sounding. Kawaoka confirmed and filled in the picture about a mutation we already knew about, which is why he looked at it more closely in this paper. As far as we know the suspicion that a mutation in the PB2 gene at position 627 that substitutes lysine for glutamic acid (the mutation is written E627K in shorthand) goes as far back as 1992 when Subbarao, London and Murphy showed it was needed for a bird virus to infect mammalian cells. The idea that temperature is important was reported by Massin and colleagues in 2001. The viral RNA genome is packaged inside ribonucleoprotein (RNP) particles comprised of nucleoprotein and three RNA-dependent RNA polymerase subunits, PA, PB1 and PB2. This package takes the virus’s RNA genetic material and uses it to make new viral protein and new viral genetic material. PB2 is part of this protein-making and gene replicating machine. It all gets packed up inside a viral outcoat that includes both the hemagglutinin and neuriaminidase proteins (the Hs and Ns of the various subtypes like H5N1) as well as some other proteins. This paper confirms that a switch from glutamine to lysine in PB2 makes a difference.

For some years we have been fixated on apparent differences between the cellular receptors preferred by bird flu viruses and human viruses. We have written quite a bit about it here (and here and here). But it was becoming ever clearer that the receptor story wasn’t the whole story or even the main story. Other things were involved. Early on, E627K came under suspicion. What Kawaoka and his colleagues have done is show that two H5N1 isolates taken from the same patient in Vietnam in 2004, one from the lower respiratory tract and the other from the upper respiratory tract, differed genetically in a few places, one being at position 627 of PB2. They then showed that this single change made a difference in the ability of the virus to infect cells from the upper and lower respiratory tract in the test tube and in inoculated mice. To show it wasn’t other genetic variations, they mutated that single position in each of the two isolates and showed that the biological properties of the virus switched with it: what before easily infected the lungs but not the upper tract now did the reverse, etc. It is quite elegant.

The relationship between transmissibility and infection of the upper tract is both on the giving and the receiving end. Infected cells in the upper tract are likely to shed more virus when the patient coughs and sneezes and an exposed person is more likely to expose susceptible cells. While we’ve known about this mutation for some time, this paper provides more direct evidence that the Glu-to-Lys mutation at PB2-627 affects growth in mammalian cells and the ability to infect cells in the upper respiratory tract. The effects are not completely clearcut. The avian version was also able to infect upper tract cells in some instances. The paper also shows it is not the only change involved. Other changes, as yet unknown, seem also to be important.

This work makes us more confident we are pursuing a reasonable line of inquiry, no small matter in a confusing question. But we haven’t as yet unlocked the key to what would make easy transmissibility in humans.

Comments

  1. #1 Daniel F
    October 6, 2007

    Yesterday I saw worst headlines such as:
    “Bird Flu Virus Has Mutated”
    “Bird Flu: Virus Has changed into more dangerous form for man”
    “Bird flu mutates to infect humans”
    Only bad media communication or also unfair communication to present scientific research?
    In Italy the Minister of Health released a note yesterday to assure population after the news about Kawaoka’s article.

  2. #2 victoria
    October 6, 2007

    And we wonder why Fumento has a voice???????????

  3. #3 Jon Singleton
    October 6, 2007

    Thanks Victoria, your comment cracked me up — the first real laugh in days!

  4. #4 ChuckD
    October 6, 2007

    Is seasonal flu more adapted to normal body temperature? Would fever (in a human patient) promote the growth of a flu strain which is better adapted to the higher temperature of birds? (I assume that it inhibits most pathogens.)

  5. #5 revere
    October 6, 2007

    ChuckD: I don’t know the answer to your specific questions (not sure if anyone does) but one of the problems with this finding is it leads people to ask questions like that. It is fairly certain that this pheyontypic trait (the temperature tolerance) takes its place against a variety of genetic backgrounds and it is that combination that makes the difference. Both people and mice did get infected with the Glu virus, so the mutation is not determinative. Other things are involved and they can interact with the temperature issue in complicated ways we don’t understand. So this is a sign that says “digging here” might be fruitful . . . so far. The virus keeps surprising us and things we think we know turn out different than we thought. But we do the best we can.

  6. #6 anon
    October 7, 2007

    I remember those 10 essential mutations given by
    Taubenberger et.al some years ago and that list
    of 13 mutations given some months ago.
    Mutations to make avian viruses human-like.
    E627K(PB2) is one of those.

  7. #7 anon
    October 7, 2007

    no mammals were involved to create the Qinghai-strain,
    so it’s just coincidence that this 627K evolved in birds.
    It must have some other advantage to the birds in this
    special reassorted strain

  8. #8 Rapid Heartbeat
    October 7, 2007

    Anon, so does this mean we have 11 out of 13 essential mutations, or did some revert back (if that happens).

  9. #9 anon
    October 7, 2007

    no, only a few (2-4?) have been found in
    mammals simultaneously.

    But I think every of these mutations was found in
    an avian influenza virus in _some_ mammal,
    just not simultaneously.

  10. #10 Tom DVM
    October 7, 2007

    “it’s just coincidence that this 627K evolved in birds.”

    If you think about it for a moment…this is exactly the problem.

  11. #11 Lisa the GP
    October 8, 2007

    The first thing I noticed in the pop press on this was that the viral sample was from 2004. Meaning its been ‘out there’ since 2004 and hasn’t blown up yet.

    Yawn.

  12. #12 Patch
    October 8, 2007

    Bored Lisa? I’m not sure why? Is it simply because it’s old news?

    I was particularly concerned with the statement in one of the newspapers, reportedly made by one of the researches who was “convinced the next flu pandemic would come from this strain of H5N1″. This was one of the researchers in Wisconsin…not sure which one, but the paper said they were the “leading expert”. I’ve not heard such a bold statement made publicly by any researcher. But I’ve been accused of reading things with an optimistic slant. Perhaps it’s been there and I’ve missed it.

  13. #13 revere
    October 8, 2007

    Patch: E627K has been around for a while. It is not new. It may well be that if a pandemic strain develops at some point, it will have K627 (or it may not). So this was a paper that better delineated some of the biological properties of an H5N1 with K627. The press seems to think it is a newly appearing mutant of H5N1. It isn’t.

  14. #14 Patch
    October 8, 2007

    Gotcha Revere. That makes sense.

    Thanks

  15. #15 Tom DVM
    October 8, 2007

    For what it’s worth, you can never determine an endpoint in biological systems with 100% confidence…however, you do make accurate predictions on trend lines…

    …and although we don’t know H5N1’s time frames (the same for all emerging diseases)…the historical trend line is clear, the ever expanding template both in numbers and geography is clear and the tendency of biological systems to speed with time (global warming and artic ice caps)is also clear.

    I think it reasonable therefore, to predict that although H5N1 may not be the cause of the next pandemic, it is here to stay and will at some point in the future be involved in a pandemic directly or contribute to one through recombination or reassortment.

  16. #16 Path Forward
    October 8, 2007

    In the interview about his findings (in the Australa AP article Revere cites above), Kawaoka said, “I don’t like to scare the public, because they cannot do very much.”

    I am not an expert on viral mutations, so I greatly appreciate Revere’s talent and effort at translating science into language I can understand.

    I wonder if Kawaoka knows that he is not an expert on public perception research, public disaster preparedness research, and public adaptation to new hazards? I wonder if he even knows there are fields of study that have information about the role of public fear, and the capacity for public response to risks.

    Particularly, I wonder if he knows how much the public can do to put pressure on government officials to fund work like Kawaoka’s, if the public decides it is important?

    Prob’ly not.

  17. #17 M. Randolph Kruger
    October 8, 2007

    Revere-Define genetic mutation against genetic variation pls.

    I read the Kawaoka’s stuff and to me they have proven that its able to infect the nose of a victim and like you said, upped it in the respiratory tract. But that as they say was then and this is now.

    It is obviously still able to infect, and like 1918 there are indications that this stuff is out there and they are either misdiagnosing it or deliberately in places like Indonesia. China maybe, Myanmar we would never know because they are too busy assassinating people and monks. But it fails me as I have read a good deal about the PRE 1918 convention for BF. There are striking similarities for cases and mild ones might have been actual cases.

    Disturbing that it might actually already be happening in a limited way. IMO Pan 4’s criteria has been met. What are they waiting for. The world is made up of something like 55% adults, do they think we cant handle it? Without vaccine a single mom could do much better than paying for HBO by buying food for the kids. We lose this new generation and all things come off the table. Defense, Social Security, Aid to Dependent Children, UHC… everything and only because we wont have anyone around to pay the bills. We would and will have come full circle in history. No insurance, no government bailouts, no UHC, no pension plans… all gone in under six to twelve months of a pandemic.

  18. #18 Tom DVM
    October 8, 2007

    “Particularly, I wonder if he knows how much the public can do to put pressure on government officials to fund work like Kawaoka’s, if the public decides it is important?”

    /:0)

  19. #19 Path Forward
    October 9, 2007

    Tom at 10:26:

    Sorry — I was a bit obscure.

    Many of us are trying so hard to raise public alarm (and I mean alarm, not terror and not mere concern) about a sooner-or-later mild-or-severe pandemic-to-be.

    But many experts seem to think the public has no role. They picture the public in a passive role while they, the experts, figure out what to do.

    Well, unless the experts are spending their own money on their research, at least some of their budgets are likely to come from public funds. In a democracy, like that of the U.S. and your country, public pressure can influence budgets. A well-informed and an appropriately-alarmed public will demand more pandemic preparedness than a passive, complacent, oblivious, fatalistic, or hopeless public.

    That’s why I always jump on officials and experts who are so lacking in imagination that they cannot picture a role for the public, and they cannot imagine that it is proper to scare people about scary prospects that need attention, resources, individual planning and societal planning.

    Hope that is clearer.

  20. #20 anon
    October 9, 2007

    I haven’t seen Kawaoka’s arguments, why E627K
    implies pandemic earlier or later.
    I can’t see why the virus is more mammalean than
    that of 1997.
    I can’t see why the Qinghai strain is more likely to
    go pandemic than e.g. the Indonesian.
    Sorry, but for me Kawaoka doesn’t make much sense.

    ————————
    October 8, 2007
    team of researchers from the University of Wisconsin-Madison
    led by virologist Yoshihiro Kawaoka of the UW-Madison School of Veterinary Medicine
    say it is “only a matter of time” before the virus takes the final steps.
    ”The viruses that are in circulation now are much more mammalian-like than the ones circulating in 1997,”
    “The viruses that are circulating in Africa and Europe are the ones closest to becoming a human virus.”
    However, Kawaoka and other flu researchers are convinced it is only a matter of time, as more humans and other animals are exposed to the virus, before H5N1 virus takes those steps and evolves into a virus capable of causing a pandemic.

  21. #21 Tom DVM
    October 9, 2007

    Thanks Path Forward. I completely agree.

  22. #22 Patch
    October 9, 2007

    Anon,

    That was the article I was referencing earlier (or meant to).

    I found that quite disturbing. I wonder if Kawaoka stated, literally, that they were “convinced it is only a matter of time” for H5N1.

    The way the piece is written, it seems to attribute the statement “It is only a matter of time, before H5N1 makes the final steps” to Kawaoka. I’m not even sure that Kawaoka describes the “final steps” in detail. I thought this was primarily about E627K. And about E627K being one “mammalian factor”.

    Is this poor writing, or is Kawaoka convinced that E627K is one of the inevitable steps to an H5N1 pandemic.

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