More about the adapting bird flu viruses

Stories on the wires this weekend highlight a new study published in the Proceedings of the National Academy of Sciences (PNAS) suggesting that some bird flu viruses are adapting to the human respiratory tract, thought to be a prelude to increased transmissibility and possibly ushering in a pandemic of influenza in humans. We need to sort out a number of things here, beginning with the idea that "avian influenza viruses" are mutating in a way woy to make humans more vulnerable. Let's take it apart.

First, influenza. Influenza can either be a syndrome (a package of clinical symptoms and signs) or a disease. As a syndrome we encounter it in the technically defined Influenza-like Illness (ILI). ILIs are defined by the presence of fever, fatigue, cough, and other symptoms. Most of them are not the disease influenza but disease caused by non-influenza viruses, like respiratory syncytial virus or adenovirus. The disease influenza id defined by its cause, infection with the influenza virus, a virus belonging to a family of viruses containing RNA as their genetic material. Three of the five members of this family infect cells in birds and other animals, including humans. The first of this group of three, influenza A, has many different variants, much like the animal "dog" has lots of different kinds of dogs, with each kind of dog in turn having lots of variants in coat color, size, etc. In the case of influenza A, the counterpart to the different breed of dogs is called a subtype (H5N2, H3N7 are both subtypes), while the different variations in each breed are called strains (one sees the word "strain" sometimes used for subtype, although this is not good practice). Most variants of influenza A can infect birds, so in the strict sense most influenza A viruses are avian influenza viruses. Some of them also infect humans and other animals like horses and dogs. They frequently also can infect birds, although some do not. Among the normally avian viruses that infect humans, the 800 pound gorilla in the room is the subtype called H5N1 because when it infects humans, as it has done close to 400 times since 2003, it has killed 60% of them (recent WHO compilation here). That's horrific and everyone worries what would happen if this one became easily transmissible but remained equally virulent.

But it's not the only normally bird virus out there that can infect humans. Avian influenza viruses of the H7 subtype have also done so. Cases have been reported in The Netherlands and in North America (Canada and the US). The health effects in H7 viruses are much milder than for the human cases of H5. Except in two instances the effects have been limited to conjunctivitis (pink eye). What is the difference between flu viruses that mainly infect birds and those that infect humans? We don't know, exactly, but much work has centered on the difference between a specific docking molecule (called a receptor) on the outside of bird versus human cells that permits the virus to get in. The usual story is that birds have the alpha 2-3 receptor while humans have alpha 2-6. We have covered this extensively (here, here, here) and you can read those posts and the links therein if you have desire to know some of the gory details. A lot of effort has gone into looking at these receptors in H5N1 but not that much in the H7 bird viruses that have also infected humans. The paper in PNAS is about those receptors:

North American avian flu viruses of the H7 subtype -- like the H7N3 viruses responsible for British Columbia's massive poultry outbreak in 2004 -- seem to have adapted to more easily invade the human respiratory tract, a new American study suggests.

The adaptation is still only partial and the findings do not suggest the viruses are imminently poised to trigger a pandemic. But experts say they underscore the fact that H7 flu viruses need to be watched and studied.

[snip]

Scientists from the U.S. Centers for Disease Control reported on their research on a number of H7 viruses, looking both at the types of receptor cells -- bird or human -- each was more inclined to latch onto and whether the viruses transmitted from infected to uninfected ferrets.

Of all available animal models, influenza infection in ferrets is considered to mirror most closely the course the disease takes in humans.

Human flu viruses that circulate every winter have adapted to be able to bind to the receptors that predominate in the human respiratory tract, known as alpha 2-6 receptors. Avian viruses, on the other hand, prefer the alpha 2-3 receptors found in the guts of wild birds (their natural host) and domestic poultry. Those receptors are scarce in the human upper respiratory tract.

It is assumed that an avian virus would need to make this kind of adaptation -- learning to latch onto the human-type receptors -- before it could transmit easily to and among humans. (Helen Branswell, Canadian Press)

The PNAS paper demonstrated that North American H7 viruses had changes that made them more likely to dock to human type receptors. But the story turns out to be more complicated, as usual for this virus. These studies showed what was already clear from other work. The receptors don't tell the whole story. For example, two of the European viruses had similar affinity for bird receptors but one transmitted between ferrets and the other didn't. The North American viruses had more human like affinity, but one transmitted much more easily than the others.

The senior author of this study was also involved in a recent study that showed that subtle differences in the structural topology of the receptor, not captured by their categorization as alpha 2-3 or alpha 2-6, also play a role in transmissibility. This study used other means to characterize receptors and didn't examine those structural (umbrella versus cone) differences. Each question poses new questions and there is always more work to be done.

What I get from this study is that we are still some way from understanding the underlying biology of transmissibility and its relation to receptor configurations and related matters. At this point we cannot simply look at the virus's genetic sequence to see what is going to happen. We don't yet understand the connection between the sequence and the biology. Maybe some day we will, but today isn't that day.

In the meantime, we need to remember that H5N1 is not the only normally avian virus out there that can potentially cause easily transmissible human infection and to which we have little prior immunity. Of course if some H7 virus comes out of birds and causes a pandemic of pink eye it won't be a catastrophe. But with this virus you can't count on that. And in the case of the H7N7 outbreak in The Netherlands, there were 80 plus cases of pink eye, but one person died of respiratory failure. That's a case fatality of a little over 1%, slightly more than we have with today's seasonal influenza.

Which kills an estimated 36,000 people a year in the US. Just thought I'd mention it.

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Revere, Niman posted up about the removal of the sequence data for the case(s) above. Very coincidental. I pulled the information on the removal and it stated that the authors couldnt confirm the origination of the organism. Does that happen often?

The world is full of conspiracy theorists but PNAS publishing the above, then this thing gets pulled within almost hours of that even gives me pause. If we are to believe that there is a behind the scenes activity we have to know what the processes are. Smoke where there is no fire or the smoking gun?

By M. Randolph Kruger (not verified) on 28 May 2008 #permalink

Randy: Yes, it happens. I don't know the frequency. There is no way to know why at this point but the PNAS paper covered it so it isn't a cover-up as far as I can see. You can make more out of something than it is and I think this might be such a case. But at this point I don't see pulling the sequence as having any consequences for public health. In fact the bottom line of the PNAS paper is that the sequences don't tell the whole story. Of course I assume Henry feels differently. Difference of opinion.

I'll take your opinion Revere. Thanks for the explanation.

The H7N2 virus outbreak in the United Kingdom one year ago this month had four confirmed human infections associated with only two reported confirmed outbreaks in poultry.

Three of the four reported [emphasisis on reported] confirmed cases were detected after being hospitalized for treatment.

The two confirmed cases hospitalized for treatment of respiratory symptoms were treated in hospital for periods of 5 days and 7 days respectively.

If H5N1 produced this same proportion of human cases from spill-over infections, we would be in very deep trouble ...

By elephantman (not verified) on 29 May 2008 #permalink

It once again appears that humanity has been most fortunate to have avoided an influenza pandemic for the past forty-years.

My uneducated advice, don't let your guard down. It's been my experience that when the tide appears to be residing and at an all time calm is the moment when the shit hits the fan.