Flu biology: receptors, I

The need for better information about the science of avian influenza is urgent. But science is a slow process, or at least slow relative to an urgent time scale, even in times of rapid advances in technology. Even so, while we are waiting for the other shoe to drop, we continue to learn and unlearn about the influenza virus. One major gap has been understanding where humans have cells with receptors for bird flu viruses. A new paper published online last week in The FASEB Journal is finally providing some information. As usual, it is both informative and confusing. To understand what it is and is not saying we'll need to do a little review of the biology. We'll do this in two parts. The second post, tomorrow, will provide details of the FASEB paper (FASEB is the Federation of American Societies for Experimental Biology).

First a review:

Host cells (in this case, human cells) don't usually sit around naked. They've got clothes on. We explained this in excruciating detail in a series of posts earlier (see here, here, here and here). Here's a short recap. The raw cell surface (its bare skin, so to speak, the cell membrane lipid bilayer) is clothed with a "lawn" of hairy protein threads sticking from and through it. The proteins are decorated with complex sugars (collectively called glycans) and the combination is called a glycoprotein. The sugars can be of different kinds and can be attached in different ways. Thus cells that would otherwise look pretty much the same when naked (a bag made of cell membrane) can look very different when clothed. This is an interesting biological tactic, so let's pause for a minute to consider it (just for fun).

All cells have the same genetic endowment, encoded in their DNA. What makes one cell different from another is its ability to turn some of the genes that make proteins on or off in various combinations. The genes make proteins by translating the code sequence into an amino acid sequence. A protein is just a bunch of amino acids strung together. Since there are a lot of genes there are a lot of possible combinations, too, most of which are non functional or never used. But what's left is more than enough to produce lots of different kinds of cells, even though they are all starting with the same inventory of genes. They employ the same genes but in different ways.

It turns out that's only a fraction of the information space available to cells. People don't (usually) sit around naked either. We wear clothes. Our choice of clothes is usually not genetically determined but responds to things that occur in and around us. I'll just leave it at that. And just like people after they are born, cells can put on all sorts of clothes. The change in appearance from wearing a different set of clothes is called post-translational modification. It occurs without any change in the genetic sequence or its expression by translation into proteins. Adding complex sugars to proteins produces the most abundant source of post-translational modifications we know of, enormously increasing the "information space" available to a cell. What does this have to do with pandemic influenza?

The different sugars that decorate the proteins on the cell surface and the specific way they decorate that surface are the ways that things outside the cell tell one kind of cell from another. This ability is biologically important. It is the way other cells or hormones, for example, are able to interact with a particular cell. But pathogens, like viruses, bacteria and fungi have co-evolved to exploit those same recognition markers for their own purposes, just like a burglar uses a window you use to look out or provide fresh air to get in. In particular, the influenza virus looks for cells with a specific sugar attached in a specific way, and when it encounters it as it is randomly floating around, it sticks to it, initiating further processes which result in the virus being taken into the cell. The glycoprotein the virus sticks to is called the receptor (as is the part of the virus that sticks to it).

The sugar the flu virus sticks to is one of a family of sugars with 9 carbons called a sialic acid. Sialic acid is bigger than glucose or simple sugar but smaller than the 12 carbon table sugar. The latter, however, is really two smaller 6 carbon sugars stuck together while sialic acid is a single sugar. While sialic acids are sometimes found on their own in nature, they are usually found attached to other sugars which in turn are attached to proteins to make glycoproteins (that is, they are articles of cell clothing). You can look in the earlier posts whose links are above for an explanation of the terminology, but the short version is this. Flu viruses from birds like sialic acids that are attached via something called an α2,3Gal linkage, while those more adapted to humans stick to sialic acids attached through an α2,6Gal linkage. Think of it as one liking cells with blue shirts and another liking cells in red shirts (no political implication intended). The assumption together with some supporting evidence has been that birds have cells with α2,3Gal and humans with α2,6Gal, which explains why bird viruses infect birds and usually not humans and vice versa. Pigs, it turns out, have both kinds of cells in their tracheas (windpipes), which gave rise to the "pig as mixing vessel" story of pandemic flu emergence. The pigs get co-infected and the bird and human viruses mix, producing hybrid new combinations with human liking receptors but bird infection characteristics. Presto. Pandemic. Except it doesn't seem to be that simple.

The underlying assumptions are two: that humans don't have α2,3Gal receptors in their respiratory tract or anywhere else accessible to an avian flu virus; and that without the matching receptor there won't be an infection. Neither of these seems to be true. Taking the second one first, we know that α2,3Gal liking virus can infect cells with α2,6Gal receptors, although they probably do this less easily. But maybe not, in some cases. The other assumption is also in question because we don't really have good information about what sialic acid linkages appear on human cells and which ones.

In the next post I'll give some details on this crucial question from the FASEB paper by Yuo et al.