January 4, 2012 | 6
The inside of the human body is a bacteria-free zone. Bacteria are certainly within you, but they exist only in areas that have a direct channel to the outside world, such as the mouth, intestines and the surface of the skin. These areas are well protected by a layer of cells (epithilial cells) which form a protective barrier to keep away the nasties of the outside world. That’s why there are healthy stomach bacteria, but no healthy liver bacteria. From a certain point of view your lungs and digestive tract still are the outside world, which is why bacteria can get in and live there, sometimes perfectly happily without causing any trouble at all.
Major problems start to happen, however, once bacteria get through that epithelial barrier and into the tissues of your body. Which is why the first bacteria of the new year is the oral bacteria Fusobacterium nucleatum, which has a trick to open up little doors in blood vessels. These aren’t massive holes, not big enough to cause bleeding but large enough to let it and other bacteria into the bloodstream.
This is a big issue, because once the bacteria get into the blood-stream they can travel around anywhere within the body. It’s not just the blood-vessels in the mouth that the F. nucleatum can get into, it can also bypass a lot of other cellular barriers such as the blood-brain barrier that keeps bacteria out of your brain, and the placental barrier that guards the passage of substances between a pregnant mother and the foetus.
The bacteria works by releasing a chemical which is picked up by the cells that make up blood vessels (endothelial cells) and causes the cells to become more permeable. More technically the bacterial chemical (a FadA adhesin) binds to a protein on the cells (vascular endothelial cadherin) that helps to keep the endothelial cells joined together and causes it to migrate away from the cell-cell junction. This opens the junctions up slightly and makes the whole vessel more permeable.
FadA (the bacterial chemical) is an interesting little molecule, and while it’s highly conserved in F. nucleatum and related oral bacterial species, it has been lost in many closely related species which do not populate the human mouth. This is a protein with one specific purpose – to open blood vessels – and where that function is not needed the bacteria has no need for the protein. When it’s first made by the cell it exists in a form called pre-FabA which anchors to the bacterial membrane with the soluble part (the actual FabA) on the outside of the bacteria ready to be deployed.
To test whether the FabA and the cell cadherin could bind, the researchers carried out a whole range of different binding tests (more information in the reference below). First, they did a yeast-two-hybrid screen, a sort of sciency quick and dirty method to see if two proteins can bind each other. Then they took both proteins out of the cell to see if they could bind separately, by sticking one protein to a column and seeing if it could ‘catch’ the other as it was washed through. Finally they put both proteins back in the cell with coloured markers attached to see if the coloured markers appeared in the same places. All of these results, along with the actual structures of the two proteins, suggest very strongly that they bind.
One of the most interesting tests they did was to see whether the F. nucleatum was just opening the floodgates for itself, or whether other bacteria were sneaking in at the same time. They did this by making little wells with endothelial tissue between them. Sure enough, those cultures containing E. coli along with F. nucleatum showed that both bacteria could travel through the endothelium together, whereas in cultures containing only E. coli the bacteria remained on one side of the membrane.
The researchers don’t suggest any way to combat this, they’re more interested in the exciting science, but regularly and gently brushing your teeth can’t hurt! (I should point out here that non-gentle brushing of teeth can damage the gums and open blood vessels anyway, making the clever bacterial tricks somewhat redundant)
Credit for image 1.
Reference: Fardini, Y., Wang, X., Témoin, S., Nithianantham, S., Lee, D., Shoham, M., & Han, Y. (2011). Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity Molecular Microbiology, 82 (6), 1468-1480 DOI: 10.1111/j.1365-2958.2011.07905.x