Our Bodies May Fight Infection Better by Day
Earlier this year, scientists in the UK concluded that a morning flu shot may actually be more effective than the same vaccine administered in the afternoon, suggesting that our immune responses may shift throughout the day.
Now, a new study in the Proceedings of the National Academy of Sciences has illuminated another link between immune response and our circadian clocks, the biological process that governs the body’s cycles of sleep and wakefulness: Herpes infections, it turns out, can vary in severity depending on the time of day infection — at least in mice.
The key, it seems, is that the body responds less well to infection when it is time to rest. Rachel Edgar, a University of Cambridge researcher who led the new study, explains that her team observed a tenfold increase in the amount of herpes virus when it was administered in the morning — the onset of the mouse’s rest period — compared to when the same dose was administered at night. The virus also spread more effectively throughout the body when it was administered to a resting mouse.
“I was quite surprised that it was that dramatic, because the dosing was the same,” Edgar says.
As a control, her team also infected mice that had genetically disrupted circadian clocks, and found high levels of infection across the day — no matter whether the mice were active or at rest.
The study’s findings, Edgar is careful to note, go beyond a system-level response to infection. Her team observed that individual cells infected outside the body can respond differently to infection based on the time of day.
“Every single cell in [the] body has a molecular clock,” Edgar says. “And viruses need to infect cells in order to replicate. What we went on to do was to take cells outside the body, so there’s no immune system at that point. And in fact, in those cells …we [saw] a similar pattern of variation in how well the virus replicate[d] over the time of day. So it looks to be that every cell in your body could potentially be contributing to this time-of-day effect we see in infection, not just the immune response to that infection.”
Mice are mammals, we’re mammals — how much about circadian immune responses can we extrapolate to ourselves from this study? Quite a bit, as it turns out. Cambridge researchers say the findings may explain why shift workers — whose body clocks are often disrupted and in flux — are prone to infections and chronic disease.
“What we think is likely is that people would have a more severe infection if they’re infected at the onset of their rest period, at night,” Edgar says. “And actually the [earlier flu vaccination] study goes some way to support that, because what you see with the vaccination in the morning is a stronger immune response — and that vaccination is just an inactivated influenza virus particle.”
Edgar hypothesizes that to save energy, the immune system evolved to be on highest alert when the body is active and thus more likely to encounter disease. She hopes that with more testing, medications will someday be prescribed for a certain time of day, to maximize their effectiveness.
“There is an emerging consensus that we should employ chronotherapies — using the therapies we have more effectively, depending on our body clocks,” Edgar says. “This has actually been trialed for chronic diseases. It’s been trialed for cancer drugs. If you administer the exact same drugs that we already have, but you administer them at specific times when the body is best able to utilize them, you do see a marked increase in their efficacy.”
Rachel Edgar is a Research Associate at the Institute for Metabolic Science at the University of Cambridge in Cambridge, England.
IRA FLATOW: This is Science Friday. I’m Ira Flatow. Did you get a flu shot last year? Now, can you remember what time of the day you got it? Now, it might seem trivial but hear me out here. Because earlier this year scientists in the UK concluded that a flu shot in the morning may actually be more effective than the same vaccine given in the afternoon. Same dose, different time of day seem to make a difference in the body’s response to the vaccine– some real world evidence that our internal circadian clocks seem to affect our immunity.
And this week another study adds weight to that conclusion by showing that time of day appears to affect the severity of a herpes virus infection too, at least for mice. Rachel Edgar is an author on that study in the Proceedings of the National Academy of Sciences. She’s a research associate in the Institute for Metabolic Science, University of Cambridge in the UK. And she joins us from the BBC in London. Welcome to Science Friday.
RACHEL EDGAR: Good afternoon, Ira. Thanks very much for having me on the show.
IRA FLATOW: Oh, you’re quite welcome. Fill us in what you did here. You infected mice with the herpes virus at different times of the day and then what?
RACHEL EDGAR: We did. So we actually used a natural mouse herpes virus. So that’s quite important, because you want the viral immune evasion strategies and the host immune response to the virus to be all in play. And we took the mouse herpes virus. We infected mice at two different times of day, either at the onset their rest period, which is in the morning for these nocturnal animals, or at the onset of the active period, which is at night for these animals.
And then what we did, we used a kind of transgenic version of this virus. It actually encodes a protein that emits light, and we were able to then image these mice over the course of the infection, which is about 10 days. And we were able to track both the amount of infection that we were seeing and also how well it spread throughout the body of the mouse.
IRA FLATOW: And so you found out that when you gave the mice the virus at what time it did what?
RACHEL EDGAR: So we had about a tenfold increase in the amount of virus when it was administered in the morning, which is the onset of the rest period for the mouse, compared to when we administered it in the evening. And we also found that it spread more effectively when it was administered at that time as well.
IRA FLATOW: Was that surprising– tenfold? [INAUDIBLE]
RACHEL EDGAR: Yes, I was quite surprised that it was that dramatic. Because also the dousing was the same. And as a control for that, we took mice at which have disrupted circadian clocks. We’ve knocked out a gene called BMI1, which is a key clock component. And those mice have no circadian rhythms. And what we see with those mice is that when we infect them at different times, it no longer matters what time we infect them. You see high levels of infection across the day at that point.
IRA FLATOW: So then they circadian rhythm then obviously has some influence on the mice’s immune system.
RACHEL EDGAR: It does. There have been quite a lot of recent studies looking at this, looking at how the circadian clock interacts with the immune system. And they do seem to find that at the onset of activity, the immune system is primed for attack. Whereas at the onset of rest, it can undergo regeneration and repair at that point. So we think that’s definitely a component of what we’re seeing.
But something that people maybe aren’t so aware of as well is that every single cell in your body has a molecular clock. Every single cell in your body can tell the time using its clock. And viruses need to infect cells in order to replicate. And what we additionally went on to do was just to take cells outside of the body– so there’s no immune system at that point– and infect those cells at different times of day. And we see a similar pattern of a variation in how well the virus replicates over the time of day. So it looks to be that every cell in your body could potentially be contributing to this time of day effect we see on infection, not just the immune response to that infection.
IRA FLATOW: Wow, I’ve never heard about that. You hear about the body but not individual cells. How much of this can we extrapolate to people from it to be working in mice?
RACHEL EDGAR: So this is where it gets slightly more complicated. Because what you have in the body is you have a central clock in the brain, and that sets the time and coordinates the clocks in all of your different peripheral tissues. In mice and in humans, the central clock is set at the same time in those two organisms. But how those central clocks then set the peripheral clocks is inverted. It’s opposite because mice are nocturnal. And so they have different challenges to us at night.
And because it’s inverted in peripheral tissues such as your nose, your airways, your skin– so places where viruses are initially going to infect– what we think is likely is that people would have a more severe infection if they’re infected at the onset of their rest period at night. And actually, the study you mentioned in the introduction there goes some way to support that. Because what you see with the vaccination in the morning is you see a stronger immune response to that vaccination. And that vaccination is just inactivated influenza virus particle basically.
So if you get a stronger immune response in the morning, you’re likely to get less severe disease. So it correlates quite nicely with our study.
IRA FLATOW: Is there some evolutionary reason why the immune system might vary in vigilance over a 24-hour period?
RACHEL EDGAR: So, as I said, this is something that sits under investigation. Maintaining an immune system that obviously you want it to be able to respond no matter what, but it’s very costly with regards to the energy it takes up. So actually, there is probably some evolutionary benefit in having an immune system that can be more poised for attack when you’re more likely to encounter diseases, so when you’re just about to be all active and then as opposed to continuously having it on a state of high alert.
IRA FLATOW: This and this evidence about the time of day being important for getting vaccinations– as I suggest, we need to test drugs for the best time they should be taken.
RACHEL EDGAR: I was suggest that’s a very good idea. There is a kind of an emerging consensus that we should employ– chrono-therapies is the term– so using the therapies we have more effectively, depending on our body clocks. And this has actually been trialed for chronic diseases. It’s been trialed for cancer drugs.
And so if you administer the exact same drugs that we already have but you administer them at specific times when the body is best able to utilize them, you do you see a marked increase in their efficacy. So yes, I would suggest this is a very good idea to try all this in antivirals, and I think it’s something we’re hoping to look at in the future.
IRA FLATOW: Let’s talk about the virus– the herpes virus, itself. It’s a very really interesting and tricky virus and an ancient one too. And it’s very widespread throughout the animal kingdom, isn’t it?
RACHEL EDGAR: It is, yes. So it’s a very, very ancient virus. And that, of course, means it’s been co-evolving with us. It’s probably the common ancestor of all the herpes viruses. Its probably about 570 million years ago or so– so before the emergence of vertebrates. So we’re talking about an incredibly ancient virus. I could say the lowest organism that is herpes virus-like particle has has been discovered in is Pacific oysters. That was 2005. They discovered a herpes virus infecting oysters.
IRA FLATOW: Wow, so it’s– well, it’s amazing. A few months back, we talked about a very interesting study that said amyloid plaques might be the body’s way of responding to infection in the brain and that years later might lead to Alzheimer’s. And the herpes virus was one of the possible infections they referred to as a possible culprit. Do you have any thoughts on that?
RACHEL EDGAR: Well what herpes simplex virus, which is the virus that normally causes cold sores– what that does is, like all herpes viruses, it establishes a persistent infection in the body. And it does this in peripheral nerves, so nerves in our peripheral tissues, generally. And then from there, periodically reactivates. Now in a very small number of that cases– about 1,500 per year in the states– you get a central nervous system severe infection where you get a lot of inflammation. That’s called encephalitis.
Now, what they think might be going on with Alzheimer’s is that herpes virus, as you age, it’s more likely to spread to the brain not in that very severe way that you see with encephalitis. But it spreads to the same parts where you see degeneration with Alzheimer’s, so the frontal lobes and hippocampus. And so this was maybe one of the first clues– is that encephalitis, the severe herpes infection in the brain, and Alzeheimer’s– it’s the same regions of the brain that are affected.
And it’s interesting. So you see an approximately 12 times increased risk if you have herpes virus infection in the brain if you have a very specific genetic susceptibility to it anyway. So there’s an interaction between your genes and your environment– in this case. you infection status. And there’s definitely an immune component to this or an inflammatory component to this. Obviously, if you got to an active– even if you got a low level activation of the herpes virus, the immune system will respond to that. And the response is inflammation, and this is thought to be, then, contributory to the cognitive degeneration that you see with Alzheimer’s.
IRA FLATOW: Do you have a lot of respect for herpes virus?
RACHEL EDGAR: I do. I’m a big fan. I know I probably shouldn’t say that. But they are a fascinating pathogen. Because as I said, they’ve evolved with us over such a long period of time. What you see is these amazing immune evasion strategies. They’re very sneaky.
So they are able to counter what the immune system throws at them and subvert the immune system so they’re able to persist for a lifetime. And so they have been many interesting strategies to do this, and we’re only really scratching the surface. I know with our study we found that the herpes virus was actually able to manipulate the clock. So it wasn’t just the virus went in at a time of day and that was that– into the cell.
We actually found it attempted at all times to manipulate the clock. And it was just how successful it was in doing that. So it tried to shift the clock to an active phase, which is pretty astounding really given you’re only talking about 100 genes within the virus. So it’s a pretty complete takeover.
IRA FLATOW: Well, Dr. Edgar, you’ve given us something to think about this weekend. Thank you very much for taking the time to be with us today.