Study finds that the time of day influences susceptibility to infection

The findings stem from the University of Cambridge-based METACLOCK project and have been published on 15 August in the ‘Proceedings of the National Academy of Sciences’. Importantly, they may help to explain why shift workers, whose body clocks are routinely disrupted, are more prone to health problems, including both infections and chronic disease.

Following infection by a virus, the virus hijacks the body’s machinery and resources found within cells to help it replicate and spread throughout the body. However, the resources available to facilitate the virus’ ability to replicate fluctuate throughout the course of the day. This is partly in response to our circadian rhythms, in effect, our body clock. Circadian rhythms control many aspects of our physiology and bodily functions, ranging from sleeping patterns to body temperature, and from our immune systems to the release of hormones. These cycles are controlled by a number of specific genes, which include Bmal1 and Clock.

To test whether the human body is more susceptible to infection at certain times of the day, the Cambridge researchers compared normal ‘wild type’ mice infected with the herpes virus at different times of the day, measuring the levels of virus infection and its spread through the body. The mice lived in a controlled environment where 12 hours were in daylight and 12 were dark.

They found that virus replication in mice infected at the very start of the day (equivalent to sunrise, when these nocturnal animals start their rest phase) was ten times greater than mice infected ten hours into the day, when they transition to their ‘active’ phase. When the research team repeated the experiment in mice lacking the Bmal1 gene, they found high levels of virus replication regardless of the time of infection.

‘The time of day of infection can have a major influence on how susceptible we are to disease, or at least the viral replication, meaning that infection at the wrong time of day could cause a much more severe acute infection,’ commented Professor Akhilesh Reddy, the study’s senior author. ‘This is consistent with recent studies which have shown that the time of day that the influenza vaccine is administered can influence how effectively it works.’

Additionally, the research team found similar time-of-day variation in virus replication in individual cell cultures, without influence from the immune system. Abolishing cellular circadian rhythms increased both herpes and influenza A virus infection, a dissimilar type of virus (known as an RNA virus) that infects and replicates in a substantially different manner to herpes.

‘Each cell in the body has a biological clock that allows them to keep track of the time and anticipate daily changes in our environment,’ said first author Dr Rachel Edgar. ‘Our results suggest that the time clock in every cell determines how successfully a virus replicates. When we disrupted the body clock in either cells or mice, we found that the timing for infection no longer mattered - viral replication was always high.’

Armed with these findings, the research team have suggested that shift workers, due to working on some nights and then resting on others, could be prime candidates for receiving the annual flu vaccines.

As well as the daily cycle of activity, Bmal1 also undergoes seasonal variation, being less active in the winter months and increasing in summer. This has led the research team to speculate that this is the reason why certain diseases, such as influenza, are more likely to spread through the general population during the winter months.

Finally, the research team also discovered that herpes viruses are able to manipulate the molecular ‘clockwork’ that controls the body’s circadian rhythms, allowing the virus to spread faster and further. This is a process similar to the one used by the malaria parasite, which is known to synchronise its replication cycle with the host’s circadian rhythm, allowing for a more successful infection.

The METACLOCK project has received around EUR 2 million from the European Research Council (ERC) and is due to conclude in September 2016.

For more information please see:
CORDIS project page