Thursday, December 27, 2007

RBD: Looking For The Sweet Spot


# 1415





One of my readers requested a simplified explanation of RBDs (Receptor Binding Domains).   Thanks, Indigo, for the question.  I hope I can do it justice.



With apologies to real scientists and virologists worldwide, what follows is a simplified explanation of how a virus binds to human receptor cells.





One of the barriers that have prevented H5N1 from becoming a pandemic strain is believed to be its ineffective binding to human receptor cells.   It may not be the only barrier, but it is a major one.



Different viruses have an affinity for different types of cells.  That is why most viruses are selective as to what organ systems they attack, or even what species are susceptible.  This explains why a virus might affect a dog, or a cat, or a bird, yet not affect humans. 



This species selectivity is known as a `host range'.  Viruses generally have a fairly narrow host range.



So how does a virus `know' which cells it can attach to, and what hosts it can infect?



By the combination of sugar molecules on the host cell's surface.






Yep. Sugar.


Animal cell membranes are comprised of a lipid bilayer with lots of strands (or chains) of sugars (carbohydrates), proteins, and fat molecules poking through them.  



These carbohydrate molecules, some being glycolipids (carbohydrate and fat) and others glyoproteins (carbohydrate and Protein), form a dense sugary coating to all animal cell membranes.



There is, however, absolutely no truth to the rumor that beneath this sugar coated lipid bilayer lies a chewy caramel center.  



But I digress . . .




Since there are a lot of different sugars, there are a lot of combinations to be found.  The most accessible of these sugars for a virus are the ones at the tips of these chains, where a special sugar called sialic acid is often found. 



Now, not all sialic acid molecules are the same.  Essentially, they are identified by what molecules they are attached to, and how they are attached.  It's complicated, and well beyond my pay grade (and ability) to explain further. 



Suffice to say there are two special sialic acid configurations that are of particular interest to us when dealing with Influenza; the α-2,3 and the α-2,6 combinations.



Influenza viruses, you see, are adapted to attach to specific sialic acid configurations.  



The H5N1 virus  currently has an affinity for the α-2,3 receptor cells.



These α-2,3 cells are plentiful in the gut of birds, and so the bird flu virus is well adapted to infect avian hosts.   The virus is most efficiently spread via bird feces due to its preference for the cells that line the intestines of birds.



The H5N1 virus has spikes on its surface, which it uses to attach to receptor cells. These spikes are like keys, and the receptor cells are like padlocks. 



If the key doesn't fit the lock, it doesn't open. 



It takes only small amino acid changes, however, to modify the key to fit new locks. The area of  H5N1's genetic sequence that determines what type of cell it can attach to is known as the RBD, or Receptor Binding Domain.  



We humans have relatively few α-2,3 receptor cells in our respiratory tract, which may explain why so few  humans  have contracted the virus.  Most of the epithelial cells lining our upper airway and lungs are of the α-2,6 variety.


That has been, thus far, our good fortune.


Human influenza viruses are adapted to α-2,6 receptor cells.  That is why the virus is so contagious. 


The concern is that a minute change to the RBD (and we could be talking one or two subtle amino acid changes) could change the H5N1 virus so that it readily attaches to an α-2,6 receptor cell.


At that point, the virus may well become easily transmissible between humans, and a pandemic could begin.


This is one of the reasons why scientists fret about the lack of sequence sharing between nations.   In places like Indonesia, where we haven't gotten much in the way of samples in a year, changes could be occurring to the RBD that pave the way to it becoming a pandemic strain. 



Aside from birds and humans, other animals have been susceptible to the H5N1 virus, and this is worrisome as well.  Avian viruses have never before been known to affect such a wide host range, infecting cats, dogs, ferrets, and other mammals. 



Whenever a virus jumps species, even if it isn't directly to man, it is time to take notice.  It shows the virus is mutating, evolving, and `starting to learn new tricks'



Pigs have both α-2,3, and α-2,6 receptor cells, which explains why they are susceptible to both human and avian strains of influenza, and why we worry about them becoming a `mixing vessel' for different flu strains.



Obviously, given the amount of infected poultry in the world, and the amount of human interaction with sick birds, if the virus were easy to catch we'd be hip deep in human cases.   We aren't. 



Maybe we get lucky, and the H5N1 virus never acquires the ability to attach to α-2,6  receptor cells.  In that case, a pandemic is unlikely.



But with every new human infection, and particularly with each new cluster, the potential for the virus to adapt to the α-2,6 receptor cells is real. 



It could theoretically do so through antigenic shift, a process whereby the virus makes a faulty copies of itself during the replication phase, introducing mutations.   Most of these mutations are evolutionary dead ends and result in a non-viable virus.



But a bigger, badder and improved virus is always a possibility.



The H5N1 virus could also, through a process known as reassortment, swap segments of genetic material with another flu virus (perhaps in a pig), and pick up the ability to infect α-2,6 cells.   


And lastly, although controversial, a virus may pick up amino acid changes via recombination, where individual pieces of viral genes are swapped, not whole segments.



The H7 avian flu viruses, while not as virulent as the H5, appear to already be easily transmitted between humans.  Recent outbreaks of the H7 virus in Vietnam and Korea, areas where the H5N1 virus are endemic, are therefore genuine causes for concern.  If the H7 and H5 viruses were to simultaneously infect the same host, a new hybrid could emerge.


Bottom line: These changes could occur today, tomorrow, next year . . . .  or they might never happen.



It all depends on whether this virus can find our sweet spot.