Effect Measure

Then avian viruses started to infect humans and we took another look. The story changed. Humans did have α2,3NeuAc receptors but they were deep in the lungs. In order for an H5N1 virus to get that far down it would have to be in aerosol form and the prevailing view was that it was expelled from another flu victim in "droplet" form, i.e., in infective particles too large to get down deep in the lungs where the cells with the right receptors were located. Hence H5N1 was not likely to be easily transmissible for that reason. There were a couple of well publicized papers to that effect and much was made of the explanation in the news. We discussed it here and registered our reservations based on the fact that there were at least two other papers showing that H5N1 was binding to ciliated cells in the respiratory tract and they are only found above the deep lung.

Now further confirmation has come that the old story is, well, just a story. In a new paper in Nature Medicine by Nicholls JM, Chan MC, Chan WY, et al. (7 January 2007; thanks to SW for the .pdf) it appears that both H5N1 and H3N2 bind and replicate quite well to tissues in the upper respiratory tract. The paper also confirmed the previous findings that H5N1 and H1N1 bound to the type 2 pneumocytes deep in the lung and even to the wandering policemen of the immune system there, the pulmonary alveolar macrophages. The earlier paper had purported to show that the same binding didn't happen in the upper tract, and herein lies a cautionary tale. We noted in our earlier post that the researchers had not actually assayed the receptors in the lower and upper tract but had instead used a probe, called a lectin, that is known to bind to specific α2,3NeuAc receptors. The specific leptin used in that work is called MAA2 and indeed the new paper verifies that it binds well to the cells in the lower tract but not in the upper. But there is another form of leptin, MAA1 that does bind to α2,3NeuAc in both upper and lower tract cells. Why the discrepancy?

It turns out that MAA2 binds most efficiently to cells where the "further in" units on the glycoprotein are different. For MAA2 and MAA1 it turns out that it is not just the terminal linkage that determines whether the lectin will bind but the next one in as well. For MAA2 the link is to the 3 position of the next sugar and for MAA2 it is 4 position. So the use of MAA2 as a probe in the earlier work missed the ability of H5N1 to bind in the upper tract. Science is hard.

What's the significance of all this? First, it destroys the tidy receptor difference story as being the explanation for host specificity. The ability to bind to α2,3 or α2,6 may still be important but not quite in the ways we thought and clearly there are other factors involved we don't understand at all. Second, the deep lung story is down the toilet, too. This has implications for whether H5N1 is transmitted via aerosol or droplet or both. The old story implicated droplet. That's why the virus wasn't so transmissible. The new paper puts the aerosol back on the table, at least as far as binding evidence is concerned. Third, because H1N1 and H5N1 both bind to the cells in the deep lung, the severity of H5N1 infection isn't explained by the site of infection alone. Lastly, the lack of ready human to human transmission is not explained by an inability of H5N1 to replicate in the upper respiratory tract.

Once again H5N1 shows us there is much we don't know and also that some of what we thought we knew we didn't.