Hal Drakesmith: Iron and Infection
Pathogens can escape recognition by the immune system, but they require iron from their host to grow and spread. If iron availability is high, infection can progress more rapidly. Diverting iron away from invading microbes slows their growth, giving time for our immune mechanisms to clear the infection. Manipulating iron transport might lead to new strategies to combat infections.
Q: We know that iron is especially important for our red blood cells and that a lack of it leads to anemia, is iron important in other functions in life?
HD: Yes it is. I think to understand why, you have to look at the properties of iron. The nucleus of the atom of iron is incredibly stable and that means that it's often formed at the end point of nuclear fusion reactions in the stars where the elements are made. As a result of that, iron is a very abundant element and because it's very abundant it's around and all over the place and it could be acquired for use in life. The chemistry of iron is also very interesting: it's able to shuttle electrons, gain or lose an electron very easily and this means that it can be involved in catalyzing chemical reactions. It's also able to form lots of different types of bonds so it can bind lots of things. So its abundant, it's got interesting chemistry, these properties really led it to being incorporated into life as life developed on Earth. For instance it's involved in oxygen binding in red blood cells as you referred to, but in DNA synthesis and also in the generation of energy.
Q: How does iron availability influence an infection?
HD: The processes that I've just described that iron is involved in DNA synthesis, generation of energy and oxygen carrying and so on are so fundamental they are actually conserved right across different forms of life. It means not only us, humans, rely on iron for these processes but the things that infect us do too. The amount of iron that's available for a microbe as it infects us is going to influence how that grows and divides and causes disease in us. This has been known anecdotally for a long time. There was a classic case in the 19th century of a French doctor who believed he was treating somebody who was anemic and iron deficient and he gave this person iron. But in fact this person was infected with tuberculosis which was latent and sleeping but still able to cause an anemia. Feeding the person iron in fact fed the tuberculosis iron and the disease grew and manifested itself with unfortunate consequences.
Q: What happens in important infectious diseases like HIV, malaria and hepatitis C?
HD: The details are a little bit murky but nevertheless we can go forward and explain it a little bit. With the case of HIV the mechanism of an association between iron and the disease is particularly difficult and obscure, but we can say that there are a few good studies that have suggested the more iron there is available the worse the HIV disease becomes and can progress to Aids a bit more quickly. For Malaria we know that the plasmodium parasite really requires iron to proliferate and grow. This is true both when it's infecting the liver and when it's infecting red blood cells, when you actually get clinical malaria. And again there are some studies which strongly suggest that the more iron availability there is the worse Malaria can get. For Hepatitis C virus it's a bit clearer, more iron accumulation in the liver is toxic, and this toxic effect of the iron adds to the damage that the virus is also doing to the liver and worsens disease.
Q: What are the most important lines of research that have developed over the past 5 or 10 years?
HD: You might need to step back a bit to understand this. So, in the 1930s it became clear that the way that we maintain our iron levels at a reasonable constant level is to regulate our absorption of iron from food through the diet, rather than regulating excretion. What happens after that is the iron comes through the gut and into the blood and then it's transferred to the tissues in the body where iron is needed, in fact most of this is the bone marrow, most iron goes to the bone marrow and gets incorporated into red blood cells. And then the red blood cells circulate around and do what they do but they have a finite lifespan and when they get a bit old, when the get a bit knackered, they get eaten by cells called macrophages. The macrophages break down the protein components, but they recycle the iron back into the blood where it can go back to the bone marrow and make new red cells. That was known. In the last 5 or 10 years, what's changed: the crucial development has been we now understand the molecules that control this flow of iron and in fact it comes down to a relatively simple process. There's one protein called Ferroportin which helps getting iron into the blood from the diet across the gut and the same protein Ferroportin releases iron from macrophages back into blood as part of this iron cycle. The second small peptide called Hepcidin stops both of those processes, the impart of iron from food and the recycling of iron from macrophages by binding to Ferroportin and blocking it. So fluctuations of the small molecule Hepcidin can control exactly how much iron we have in our body but also where the iron is in our body.
Q: Could your research lead to new strategies to combat infections?
HD: Because microbes really need iron, trying to deny iron to the pathogens as they are infecting us is probably a good way of thinking about how to stop them growing. The new opportunity I think is that because we can understand Hepcidin now and we understand the iron flow, we might be able to more precisely divert iron away from particular pathogens. An interesting thing here is that different types of microbes prefer different places within us to live. For instance, Malaria likes to live in the liver and then in the red blood cells, Hepatitis C virus likes the liver, Tuberculosis for instance likes Macrophages. All these different cell types have different ways of acquiring iron but we can control the flow to the different tissues potentially by altering how we control Hepcidin.
Q: Why does your line of research matter? Why should we put money into it?
HD: I think we need as many different strategies as possible to try and combat infections which are very important and cause an enormous amount of disease burden in the world. So one advantage of thinking about reducing iron availability to microbes as a potential approach is that microbes as we've discussed in the previous answers really need iron for very fundamental things in order to grow and they cannot escape that requirement. We know that microbes can escape other types of defense mechanisms that we might have, for instance they can avoid immune detection and they can mutate even if they have been detected by the immune system, but they cannot get away from the fact that they need iron to grow. If we were able to really divert iron precisely and safely away from our invading pathogen then it would slow its growth. That would give time for the immune system to come and recognize and kill it. Time is a really crucial factor here. In fact many antibiotics work not by directly killing bacteria but they are bacteriostatics: they stop the growth and they actually give time for the immune system to come and kill the infectious agent. But as we know you can get antibiotic resistance and you can avoid the immune system as well. But you can't avoid as a pathogen the fundamental requirement for iron.
Q: How does your research fit into translational medicine within the department?
HD: I think I'd like to emphasize the collaborative nature of what we do. We have to work with lots of other groups who are experts in particular infectious diseases and what we bring to that is our expertise on iron metabolism. So we get together and this provides us with an opportunity to liaise with lots of other members of the department to come up with new complimentary strategies to think about limiting infectious disease burdens which hopefully will help along with the other approaches the department is taking.