Wrestling with time: viruses vs. the host circadian clock

Just a reminder if you travel from UK to New Zealand, you don’t really need to re-adjust your watch as it's a 12-hour time zone of these two countries. However, this is not so true for your body clock – it would need to re-align to the local time through a rather unpleasant experience, yes, jet-lag.

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Our daily activity is timed in a 24h manner – the circadian rhythm controls our daily sleep/wake and feeding/fasting cycles as well as blood pressure and body temperature fluctuations. Beyond these behavioural and physiological activities, the circadian rhythm reaches into nearly every single cell in our body and orchestrates a self-sustaining, time-regulating machinery.

At the molecular level, circadian rhythms are regulated through several transcriptional and translational feedback loops by a set of key clock proteins and genes. This internal circadian system functions in a ~24h manner and is entrained by external cues such as natural light. 

Viruses are obligate intracellular pathogens, which rely on the host cellular machinery for their replication. A growing body of evidence has linked viral infections to the host circadian system1.

Viral entry – the right time to get in

Viruses enter cells by engaging with specific proteins presented on the surface of the cell membrane, termed viral receptors. Emerging evidence shows these receptors are expressed in a circadian fashion such as those for hepatitis viruses 2,3 and this can influence the number of viruses entering cells at a certain time of day. 

Since these viral receptors have been pursued as therapeutic targets, the impact of time-of-day administration should be considered when evaluating their anti-viral efficacy.  

The rhythm in immunity against pathogens

Once inside the cells (infection happened), a set of cellular innate immune sensors that recognize viruses initiate the fight against the infection. Many of these pattern recognition receptors, for example members of the Toll-like receptor family, are directly controlled by circadian factors4. 

Since circadian rhythms regulate innate immunity, circadian disruption like shift work or jet-lag may result in an increased susceptibility to diseases. It is tempting to speculate that viruses have evolved to escape the immune surveillance by replicating during times of low immune activity. 

Vaccination at the right time

Timing of vaccination can optimize our immune defences against infection. A UK multiple centre study concluded that Influenza vaccination is more efficient when administered in the morning compared to the afternoon4. 

It is important for future studies to consider this effect and to encourage precise documentation of time when vaccinating.  This could play an important role when a fast and effective vaccination is required, exactly what we are experiencing in the current COVID-19 pandemic. 

Host targeting vs. direct antivirals

One challenge when targeting viruses is their ability to mutate and escape the body’s immune system, which results in an arms race of the pathogen against defence mechanisms. Targeting the host’s cellular circadian machinery instead of the ever-mutating virus therefore provides promising treatment opportunities. 

References

1          Borrmann, H., McKeating, J. A. & Zhuang, X. The Circadian Clock and Viral Infections. J Biol Rhythms, 748730420967768, doi:10.1177/0748730420967768 (2020).

2          Zhuang, X. et al. The circadian clock components BMAL1 and REV-ERBalpha regulate flavivirus replication. Nature communications 10, 377, doi:10.1038/s41467-019-08299-7 (2019).

3          Zhuang, X. et al. Circadian control of hepatitis B virus replication. Nature communications 12, 1658, doi.org/10.1038/s41467-021-21821-0 (2021).

4          Long, J. E. et al. Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomised trial. Vaccine 34, 2679-2685, doi:10.1016/j.vaccine.2016.04.032 (2016).

Xiaodong Alan Zhuang

Researcher, University of Oxford

Circadian biology, viral infeciton, immunity and immunotherapy