Life of a pathogen: pump some iron!

Has somebody set up a miniature  weightlifting gym for microbes? Not yet, but just like you and I bacteria need iron to stay  alive. However, unlike us they don’t get iron as a supplement in  their cereal – they  have to find it for themselves. In bacteria  iron is needed to make proteins involved in vital processes such as  respiration and DNA synthesis. With the stakes so high they need specialised ways to get iron, and more often than not they have to  scrounge it from us, their human host.

Iron scavenging molecules (called siderophores) are one way that bacteria can get iron from a host. In the human body the levels of free iron are kept very low, so the  siderophores have to be very good at finding iron then hanging on to it (high affinity). Once they’ve done this they need to get back into the bacterial cell via special transporters in the cell membrane (see figure below).

So, send out some scavengers and get loads  of iron? Not so simple! Firstly,  the whole process takes a lot of energy for the cell. In E.coli it takes 4  different proteins just to make the siderophore, plus another 4 proteins and some  ATP (the energy currency of the cell) to get it back in again. Secondly, too much iron is toxic to the cell, so it needs to make sure that it only goes to all this trouble when it really needs to – in other words it needs some gene regulation.

This is where it gets clever.  Inside the cell there’s a protein called Fur (ferric uptake regulator) that keeps an eye on how much iron is in the cell and turns the genes for iron scavenging on and off. When there’s lots  of iron in the cell the iron binds to Fur. This allows Fur to bind to the iron  uptake genes and turn them off, so the cell doesn’t waste any resources or  overload itself with iron (see figure below). When there’s not enough iron in the cell there’s no  iron spare to bind to Fur, so Fur can’t bind to the DNA. This means that the  genes are active and the proteins for iron scavenging are made.

That’s a pretty good system, but a  lot of pathogenic bacteria take it a step further. When pathogens enter the body they need to spring into action to make virulence factors – the proteins and molecules that allow them to survive in the body and do all the  nasty things that they do. It would be a massive waste of energy if they made these all the time, so they need to be able to  activate them specifically when they enter a host. Bacteria don’t have eyes or GPS so they have to sense the environment to work out where they are. Low iron levels is one signal that they are inside a host, so it makes sense to use an iron  sensing protein to regulate other virulence factor genes (figure 3). For example, E.coli uses the Fur regulator to regulate  virulence factor genes for fimbriae (fibres which can latch onto human cells),  haemolysin (a toxin that breaks open red blood cells) and Shiga-like toxin (a toxin that helps E.coli cells to get inside human cells).

So, in the arms race of human vs. pathogen it seems that bacteria have found a few sneaky solutions this time. Not only have they gotten around the body’s iron restriction mechanisms, but they also use the low iron levels as a trigger for more deadly weapons.