Turning off immune cell clocks

Like many body systems, the immune system activity changes throughout the day. And by setting out to better understand our body defences’ daily rhythms, Oxford University’s David Ray and colleagues recently showed that actually turning off the clocks in cells called macrophages made them better at combating pneumonia-causing bacteria in mice. First up, does varying immune system activity mean us humans are more or less vulnerable to infection at different times of the day? Katie put this to David...

David - That's almost certainly true. We don't know that for sure for people, because clearly it's quite difficult to know if someone's wandering around when they're going to come into contact with a virus or bacteria. However, we've been able to use an animal model to test that. And we also know from doing studies in people that, for example, immunisation works differently depending on the time of day at which you're immunised. There was a nice study published looking at seasonal flu immunisation in older people, and showing that those who were immunised in the morning got a better immune response, better protection from flu, than if they were immunised later on in the day.

Katie - You've had a recent paper published, which is talking about turning off body clocks in the immune system. It seems a bit counter-intuitive. Why are you doing that?

David - So we started off with this piece of work really to try and address the role of a clot in a particular immune cell called a macrophage. So we first of all did some studies where we showed that the response of a mouse to the encounter with a very common bacterial cause of pneumonia was different depending on the time of day at which the bacteria showed up. We stopped the clock in these immune cells (the macrophages) to see if we could interrupt that time of day effect. Which we did. But then we were really surprised. First of all, we noticed that when we stop the clock just in the macrophage, all the other clocks in the mouse are working completely normally. The mouse looked completely normal, slept at the right time, ate at the right time, but was protected against getting pneumonia. In almost all the previous work that we and others have done, if you interfere with the operation of the clock - which let's be clear, it has been with us ever since bacteria emerged as a life form on the planet, all bacteria, fungi, plants, animals have all got timing systems - and almost always when you interfere with that, something bad happens. I think this is the first time that stopping the clock in a cell has resulted in a beneficial gain of function.

Katie - And what is that beneficial gain of function?

David - So it makes the macrophages change from being in a sort of rested, quiet state to being in a sort of vigilance state. So they look different and they're sort of already primed to fight off bacteria. So they move around more rapidly, they chase down bacteria more rapidly and they engulf, digest and kill bacteria more rapidly.

Katie - Do you know why their macrophages have this behaviour, this kind of restful role relative to that other activity?

David - We're always engaged in a sort of battle with the bacteria that live on us and are surrounding us all the time. The problem with having macrophasias in a vigilant state all the time is that although you get some additional protection from bacteria infection, there may be friendly fire damage to other cells, other tissues in the body. So we think what we've stumbled on here is part of the mechanism that allows the body to be primed to fight off infection at the time of day when it's most likely that infection will take place and that then naturally at the time of day when the body is less likely to be infected, the immune system switches down to a more resting state to allow tissue recovery.

Katie - Oh, I see. And is that morning versus afternoon?

David - Yes, that's exactly right. Yes. We think what's happening in the bacteria, the infection of a mouse is nocturnal (so it's active at night). We have to sort of remember that and, and sort of switch it around, to what's happening in people is that, um, it looks like the macrophages are more vigilant and more primed to fight against infection at the start of the active phase.

Katie - Does this have translational potential? Using this knowledge to benefit human health?

David - Well, potentially, yes. So at the moment the fight against bacteria is largely being won by the bacteria. There have been no new chemical antibiotics for 30 years. Multidrug resistant bacteria are a real problem. Now, if we could tap into this mechanism that we've discovered, which regulates the antibacterial activity of the immune system, we may be able to activate it or unmask it in order to allow us to use our own natural defenses more effectively.

Katie - All this assumes that your body clock is working as it should do, but if you're in hospital, that might not actually be the case and I understand you're doing a bit of work on trying to kickstart body clocks in people whose body clocks aren't working very well. Our body clock is kept in time with the light dark cycle, mainly through sunlight exposure to the eyes.

David - If people are in a hospital, they won't be getting bright sunlight. Also in hospitals, particularly in intensive care units for example, there may be no windows, there may be lights on during the night as well as during the day. And people are often fed in a rather sort of a odd way. So people can be fed continuously by using tubes into their stomach, for example. What that means is that people lose any external cues as to when it's daytime, when it's nighttime. And we think that there may be an advantage to sort of restarting the body clock in order that our immune systems, our energy metabolism can again work optimally.

Katie - These external cues, are they only relevant if you're conscious?

David - Uh, no, they're also relevant if you're unconscious. Interestingly, so the argument is that, uh, if someone is sedated, uh, heavily sedated, they may have their eyes closed for example, but there is sufficient light that still gets into the retina even if the eyes are closed for there to be a signal to the brain to tell you when it's day or when it's night. And the other way, uh, we get cues as to what time it is, is through feeding information. Our immune system, our livers and so on, are all kept in time by having food signals from the gut. And again, if people are in hospital, frequently you find that they're being fed in a continuous basis throughout the 24 hours via a tube into the stomach.

Katie - So what can you, and what are you trying to do about it?

David - At the moment, we're still gathering evidence for what sort of trials we'd like to do. Among the trials we're interested in is looking at the effects of altering light intensity and also, uh, restricting foods so that people have a distinct fed period and a fasted period, which is very much how we operate when we're feeling healthy. And well, we think one of the consequences of circadian disruption, and when we bring people into particularly intensive care units, it's a very disrupting environment, is that none of the normal systems work very well, which means that not only does it take longer to recover from whatever the original insult is, but the longer you're there, the more likely it is that other systems start to go wrong.