How fever helps you fight infections
Interview with
The headache and sore throat that accompany a cold or the flu make you feel bad enough, so why does the body make us feel doubly awful by throwing a fever into the mix and cooking us in our own skin? We knew already that some infecting microbes grow less well at higher temperatures, but now scientists in China have discovered that a higher body temperature also helps immune cells get to sites of infection more efficiently. Immunologist Clare Bryant, from Cambridge University, spoke to Chris Smith, after taking a good look at the findings...
Clare - What happens is there are a bunch of proteins produced in response to infections and other immune processes that then drive the production of molecules called prostaglandins and they cause an increase in their body temperature and that's really important for making a hostile environment for bugs. But also it seems that if you get this increase in temperature it increases your chances of surviving and recovering from infection. Very important. And it's very interesting as to why that might occur.
Chris - So basically the body temperature is set your brain isn't it? And there are chemicals released by the response to the infection that then triggers that set point upwards and we all do it. And animals do it as well, everything does. It clearly has a benefit to us.
Clare - Yes absolutely.
Chris - So what actually are the researchers in China saying in their paper? What did they do?
Clare - So what they did was they had a look at an interesting process that goes on which is you need your immune cells to actually get to the site infection site information. And in order to do that the immune cells such as T cells for example actually have to jump off the train of the circulation and get into the site of the tissue that's infected.
Chris - So they're going round in the bloodstream, these white blood cells, and they need to be not in the blood they need to be where the action is, in the actual tissues.
Clare - Yeah so they're patrolling in the blood and they need to get off and into the tissues in order to work that out. So the tissues do some very neat ways of producing chemicals that will attract these cells into the tissues but they actually need to get off, get off the train. And so what happens is that the lining vessels of the blood stream produce a bunch of sticky molecules and then the receptors in things like T-cells see these. And then what they do is they sort of stick and they roll along the blood vessel wall in this kind of sticky way, until they reach a site of infection which is indicated by chemoattractants ,so those are molecules that attract these cells in. And then these cells actually move from the blood vessel wall into the tissue and that process - stick, roll and invade.
Chris - That is how the tissue recruits the cells out of the bloodstream it makes the blood vessels in that region that's got the infection in it more sticky than normal so the cells can gain a toehold and then get in. But how does the temperature side of things come into that because we've been able to watch down microscopes that process you've just defined for many years, we knew that blood cells begin to stick better in areas where there's an infection. So where does the temperature come in?
Clare - This is the really neat thing about this paper so what they did is there is this bunch of proteins which are specifically up regulated when you get a fever, they're called heat shock proteins. And in this paper what the guys did was they showed that one of those and only one of those proteins called HSP 90 heat shock protein ninety was up regulated.
And then what it was able to do was to send a signal from the inside of the cell to the outside of the cell through a very specific protein called alpha-4-integrin which is a protein that actually makes the stickiness, it’s the stickiness receptor.
Chris - Like cell Velcro?
Clare - Exactly like cell Velcro. And so what happens is that the HSP 90 binds to the tail of the alpha-4-integrin and this up regulates on the cell surface. But even neater than that, this protein can combine two molecules of the integrin. So you get clumping of these receptor proteins and makes multiple stickiness and increases the maximum stickiness to the blood vessel wall.
Chris - So in other words you've got the area where there's an infection making the blood vessels there a bit more sticky already. We knew that. But when you add onto that the effect of the raised body temperature that's making the cells that need to go to that site of infection a bit more sticky as well. So the combined effect is going to be it's much easier for the cells to cling onto the side of the blood vessel where there is a zone of infection and then squeeze into the infected areas.
Clare - Exactly right because the alpha-4-integrin is absolutely critical for the stop and invade signal.
Chris - And now we understand a bit more about this process of inflammation, there are lots of diseases where the immune system runs amok, auto immune diseases like SLE and arthritis. Would it be possible to exploit this in order to damp down the immune system because without it we obviously need the immune system to get rid of infection but when we don't want the immune system attacking things you get all kinds of consequences.
Clare - Yeah. The really neat thing is now that we understand the mechanism involved, this up regulation of the heat shock protein 90, you can actually down regulate that, you can switch it off. And in doing that you'll then reduce stickiness and you reduce the level of immune invasion of these tissues so things like rheumatoid arthritis for example the joints will no longer be infiltrated by these T-cells and that should down regulate the immune response.
Chris - They did this in experimental mice. Do we have the same molecules in humans? Can we assume this is applicable to us?
Clare - Yes we do. The heat shock proteins are evolutionary conserved as are the integrins. So it's very likely that we should be able to target immune diseases by using an approach on this sort of molecule.
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