Do carbohydrates play a role In intrinsic immunity?

A question that has been on my mind for the last few months is this: how do viruses interact with cellular carbohydrates? You may find that a dull question but excuse me, I'm currently writing up my Ph.D and these kinds of questions can plague your mind. 

Some example polysaccharide complexity (bioweb.wku.edu)

We all know about the role of proteins, DNA and RNA and lipids in cell biology (we all learnt about this school), but what about carbohydrates, or sugars? Apart from their use in your cell metabolism, what else are they doing? Do they have a structural role? Do they do anything in the immune system? And, if so, how do pathogens circumvent this? Or how does your own cells manipulate them to prevent infection?

Some basic carbohydrate chemistry

As I said, apart from being used during respiration and as an energy store, they can be stuck on to proteins and lipids (glycoproteins, glycolipids and proteoglycans), which can then can be moulded into large, complex macromolecular structures through the use of glycosidic bonding (covalent bonds involving at least one sugar). This is similar to what is seen with amino acids and nucleotides when building polypeptides and DNA, for example. To give an example of the potential for complexity in these large sugar macromolecules: single carbohydrates (monosaccharides) can be joined together to form di- and tri-saccharides, which can in turn be sculpted into larger polysaccharide structures. With each new saccharide added comes an ever increasing number of potential new carbohydrate linkages. With each new linkage, different kinds of saccharides can be attached. And so, and so on. You can imagine what kinds of structures can be assembled using this chemistry. But for what use?

A role in immunity?

This is a question I've been thinking a lot about lately (as I said, finishing up my PhD and part of the work involved viral interactions with sugars). From my limited experience with this is that all I see are viruses using these sugars to latch onto and infect a cell. Think of how influenza uses sialic acids ( a type of sugar). These virus entry receptors, as they're called, are found on the surface of cells. But I can't imagine that these molecules are only being used for the good of our viral parasites. So what is their natural role?

Well these molecules have lots of different roles but one of their more interesting roles (my opinion) is in assembly of what is known as the cell 'glycocalyx'. I like to think of it as a sugary coat of armour. This is a layer of sugar coated proteins and lipids found on the surface of all our cells, forming a lattice-like structure where it can be easily used to alter cell-to-cell interactions, depending on its chemical composition, which as I mentioned earlier is a pretty complex affair. Not easy to go into in a blog post. One emerging function of the glycocalyx is a protective, intrinsic immunological role. It is in a perfect position to physically sift out incoming pathogens that would would like to infect our cells. Especially considering its size in comparison to some human pathogens (around 50 nm - 500 nm). It is also highly sialylated (terminally linked to sialic acids) and sulphated, making it very negatively charged. Viral membranes are also  It is a difficult barrier to traverse. For more information on virus/glycocalyx interactions see this book chapter here. And if you really want to dive into it more, see this great science consortium website (lots of free, open data).

The best picture of the glycocalyx, this time from an endothelial cell (Hubrecht.edu)

Show me the evidence. 

The paper that alerted me to this phenomenon was this: 

Glycocalyx restricts adenoviral vector access to apical receptors expressed on respiratory epithelium in vitro and in vivo: role for tethered mucins as barriers to lumenal infection.

by Stonebraker et al in the Pickles lab. 

This paper, from about ten years ago, basically describes an attempt to get a genetically modified adenovirus into differentiated human airway cells in cell culture. They find that despite expressing the viral receptor on the surface of each cell (and on the cilia), this virus still fails to infect. Something is therefore blocking infection. (Whether there is something biologically wrong with the receptor being expressed in this non natural way (it is usually found on the bottom of the cell) is unknown. Despite any of these concerns the removal of certain sugar molecules and proteins from the surface of cells allows a more efficient infection process to occur. They conclude from this that the cell glycocalyx functions to prevent virus infection. They cannot say why this occurs but postulate that it could physically bind virus particles or may physically sift them out and prevent them reaching the cell membrane where its receptor is found. The paper itself isn't clear cut but these data are presented nicely. Despite being a bit of an artificially system it makes me wonder how other viruses navigate this glycocalyx barrier? Especially for viruses that use sugars as receptors, how do they avoid binding to non-receptor molecules not on the cell membrane? 

For example, consider influenza. It is a virus covered in proteins that like to bind to certain sialic acids on the end of sugar chains at the surface of the cell. It uses this binding to stimulate cell endocytosis and fusion if it's membrane with the cells. How do you suppose an influenza virus particle navigates the glycocalyx? I really don't think we know this answer, even after then ten years since this paper was published. But I imagine that with the work of the Functional Glycomics Consortium we are going to begin to understand this a lot better.