Neisseria meningitidis is a bacteria which lives in the throats of around 30% of the human population. In most cases it causes no problems at all and just exists as a normal part of the throat microbial flora. In some patients however it can start to colonise the bloodstream and brain, leading to cases of septicemia and meningitis which are highly dangerous and can be fatal.The invasion starts with individual bacteria, which adhere to the epithelial cells that cover the inside of the throat. They then start to divide and proliferate to form large aggregated colonies. Within these colonies they are connected to each other, and to the epithelial cells, by protrusions from the bacterial cell surface called pili which are shown below for a wild-type (i.e un-genetically modified) Neisseria meningitidis:
Image taken from the reference below. The arrow points to one of the pili, and the insert shows a close-up of it.These pili are often modified by the attachment of small molecules to the pili proteins, including the molecule phosphoglycerol (shown on the right for those interested in structure)
. To test the effects of the addition of phosphoglycerol, the researchers found which gene caused the addition of this molecule onto the pili (the pptB gene), and removed it from the cell. Without the pptB gene there was still the same number of pili around the cell, but they were not clumping together as much. Instead of the thick fibres seen in the wild type above (caused by large bundles of pili) only little stringy fibres were seen. These thin spindly fibres show that without the addition of phosphoglycerol, the pili cannot clump together.This is important medically as Type IV pili bundle formation and N. meningitidis aggregation for infection are linked. Interestingly it was not the aggregation that was affected by removing the phosphoglyerol but the ability of individual bacteria to leave the aggregate to infect other parts of the body. In wild-type bacteria, the pptB gene is strongly activated only after several rounds of division within the aggregate, so it looks like the addition of phosphoglycerol acts as a switch, communicating to the bacteria that enough of them have aggregated and it is now time to leave. If the pptB is activated due to large numbers of bacteria it could act as a communication of the population density - signalling to the individual bacteria that the current location is far too crowded, and it has better chances of survival if it leaves.
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Chamot-Rooke J, Mikaty G, Malosse C, Soyer M, Dumont A, Gault J, Imhaus AF, Martin P, Trellet M, Clary G, Chafey P, Camoin L, Nilges M, Nassif X, & Duménil G (2011). Posttranslational modification of pili upon cell contact triggers N. meningitidis dissemination. Science (New York, N.Y.), 331 (6018), 778-82 PMID: 21311024
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I had a few questions Rat. Presumably pili clumping precedes aggregation and development of pathogenesis and the clumping requires the phosphoglycerol modification.
ReplyDeleteWhere does the phosphoglycerol come from? Is it host or bacterial derived?
What else does phosphoglycerol do?
Your suggestion that control of the pptB gene could inhibit infection but is it not also possible to sequester or cleave phosphoglycerol to achieve the same goal? My guess would be that this would be easier than gene level interventions is all :)
Nice post, thought and question stimulating...
@James: The phosphoglycerol is just a small molecule used for post-transcriptional modification. It's made by the bacteria. Getting it to be sequestered somehow would be very, very difficult.
ReplyDeleteControl of the pptB gene does inhibit infection, but I'm certainly not suggesting this as a pharmaceutical product! It would be pretty much impossible to try and genetically engineer bacteria in an infection. Blocking the actual modification would be more the way to go, possibly knocking out or inhibiting the protein that's responsible for adding the phosphoglycerol.