Science: Invasion of the iron-snatchers: Bacterial infection triggers a desperate tug of war deep inside the body. Simon Hadlington reports

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The Independent Online
WE SNEEZE and cough, our noses stream and our overworked lymph nodes swell. These are some of the outward signs that our bodies are trying to repel an invading micro-organism. Yet deep in our blood and tissues a more subtle battle is going on in which we are trying to starve the enemy into submission by depriving it of a vital nutrient: iron.

Our bodies contain a good-sized rusty nail's worth of iron. Most is locked away in substances such as haemoglobin and another iron-binding protein called transferrin, but a small amount circulates freely.

Bacteria, like most organisms, need iron to survive. Our bodies know this and respond to bacterial infection by immediately starting to gather up and hide any available iron circulating in the blood.

This phenomenon, known as the hypoferraemic response, is largely accomplished by the increased synthesis both of transferrin, which mops up the free iron, and a related protein, lactoferrin, which takes the iron from transferrin and stores it in the liver.

This concerted activity would seem, on the face of it, to render the blood's levels of free iron so low that no bacterial growth would be possible. But bacteria have evolved ways of confronting this challenge, and evidence is accumulating that an organism is likely to be a potential pathogen (or disease-causing agent) if it has the ability to acquire the small amounts of free iron that remain in the body's fluids and tissues.

In conditions of extreme iron stress, a genetic switch is triggered in certain bacteria which results in the production of substances that, in effect, are enormously powerful biochemical magnets with a high affinity for iron. These compounds are termed siderophores, a word derived from Greek meaning 'bearers of iron'.

Siderophores diffuse out of the bacteria and latch on to any free iron in the vicinity. They then return, laden with their precious cargo, to dock into a bespoke protein on the bacterium's surface, transferring the iron to the organism.

But not only can these siderophores home in on free iron, they can also 'steal' iron from the body's own 'magnets' - transferrin and lactoferrin.

Some organisms have evolved an even more cunning strategy for iron scavenging. Notable among these is Neisseria gonorrhoeae, the bacterium responsible for a common sexually transmitted disease. This microbe manufactures a protein on its surface that can tightly bind the body's own iron-grabbing transferrin, and remove the iron from it for its own use. In other words, it bypasses the need to produce its own 'magnet'.

Professor Peter Williams of Leicester University's department of genetics is a leading authority on bacterial iron metabolism. 'There has been an explosion in research on iron metabolism in pathogenic bacteria,' he says. 'A deeper knowledge of the mechanisms involved in iron scavenging could result in medically useful advances.'

One possibility is in the production of 'live' vaccines. The surface protein on to which the iron-laden siderophore binds is likely to be 'immunogenic' - a substance that the body recognises as being foreign and against which it can direct its immunological armoury. 'If you were to make a mutant that was defective in its ability to manufacture the siderophore but which still had these protein receptors on its surface, you then have an 'attenuated' strain of the bacterium that you could use as a live vaccine,' Professor Williams says.

Live vaccines have certain advantages over other types of vaccine, mainly because they are relatively simple to grow in large quantities, without the need for the expensive purification stages that are required if only the immunogenic fragment of an organism is being used.

Professor Williams's team is collaborating with scientists in Germany to investigate iron transport mechanisms in Salmonella. They are also working on a project with researchers at Imperial College, London, looking at the development of live vaccines.

Knowing the identity of the genes responsible for the ability to scavenge iron could also provide the basis of diagnostic tests. 'There are some organisms that cause urinary tract infections, which can, particularly in young girls, lead to severe kidney infection if it is not diagnosed quickly,' says Professor Williams. 'It should be possible to use genetic probes to see very rapidly if the organism has the genes needed for iron grabbing.'

Yet another idea is to synthesise molecules that resemble siderophores and attach to them antibiotics. This could be a way of specifically targeting the antibiotic to the virulent bacteria. 'This seems to work in the lab, but there are still experiments that need doing to show that it will actually work in a living system,' Professor Williams says.

(Photograph omitted)