What are the underhanded tactics that viruses use during infection? How might the time of day affect the body’s response to a virus? Dr Rachel Edgar, a Research Associate based at the Wellcome Trust-MRC Institute of Metabolic Science at the University of Cambridge, investigates the game of strategy and timing that has played out for hundreds of millions of years, as organisms’ immune systems defend against the unrelenting invasion of pathogens.
Like so many of the systems in our bodies, the immune system is regulated by ‘circadian rhythms’, the inbuilt cellular clocks that are found in many living things, from archaea to zebras. These clocks allow regular changes in biological behaviour, enabling organisms to anticipate and respond to environmental changes, be they beneficial or noxious.
In humans, the most obvious reminder of our circadian clocks is our daily sleep–wake cycle, but their influence is much wider, impacting hormone release, cell regeneration, body temperature and metabolism. The immune system is in its prime state when attacks are most likely and undergoes the necessary repair and regeneration when the body is resting. Research suggests that in mice, for example, the immune system is poised to respond to an oncoming invasion just before early evening. Because circadian rhythms are evolutionarily ancient, there is the real possibility that pathogens will have co-evolved to capitalise on the predictable changes in organisms’ immune systems.
Dr Edgar wants to find out if the time of day at which the body is infected affects either a virus’s ability to replicate in cells or the progression of the disease in animals. “I suspected that this would have already been looked at,” she said, “but as it turns out, with regards to virus infection, nobody has looked to see if there was a timing effect.
“The amazing thing about the clocks is how reliable they are, even without external cues. Say you were locked in a darkened room for a long period of time, you’d still have your circadian rhythms,” Rachel explained. When external cues are present, the internal clock tunes itself to make sure it is in time with regular changes in the environment, such as light–dark cycles.
Some of Rachel’s experiments involve infecting a cell or whole animal with special viruses that express luciferase, an enzyme that causes light to be emitted. The amount of light emitted can be measured, allowing her to monitor how quickly the virus is replicating or how the disease is progressing. She uses two different approaches to see how the time of day affects the virus: either she changes the time that she infects hosts or she uses a host with disrupted circadian rhythms. Circadian rhythms can be disrupted using drugs or genetic modification.
Rachel is also investigating whether viruses can manipulate our body’s clock. For these experiments, instead of using viruses that emit light, she uses cells that emit light in time with their circadian rhythms. She can then compare the patterns in light emission before and after infection to see if the virus has any effect. When looking at whether a virus is able to manipulate the circadian rhythm of whole animals, she monitors whether their behaviour changes before and after infection.
Once we understand how the viruses interact with our circadian rhythms, we may be able to use this new knowledge to our advantage during treatment, applying an approach called chronotherapy. This approach uses current drugs, but matches the times at which they are given to a patient with their biological clocks and is being researched to test its effectiveness in the treatment of cancer and diabetes, for example. Rachel thinks the same could apply when treating a viral infection: “You can potentially envisage that when you give an antiviral drug might be very important, particularly with persistent or long-term viruses.”
Rachel also suspects that how infectious we are when we have a virus may depend not only on how long we’ve been infected and how long the virus has had to replicate, but also on the time of day. If this were true, we may be able to make changes to the ways we try to prevent viral disease transmission on a population scale.
Calum is a member of the Wellcome Trust’s Graduate Development Programme.