Do viruses make your clock tick wrong?

With the Covid-19 coronavirus pandemic happening, let’s delve into one of the many clever strategies that viruses use to successfully infect their host – disruption of the body (circadian) clock.

Image credit: Apple Chew

What is a circadian rhythm?

Circadian rhythm is a natural cycle that repeats roughly every 24 hours. The circadian rhythm controls the timing of various bodily functions using external environmental signals – primarily, light and darkness. Bodily functions controlled by the circadian rhythm include sleeping and waking, hormone production, fluctuations in body temperature and many more. The master clock is located in the brain and links to a network of secondary clocks in virtually every tissue and organ. Circadian rhythms are found in most living things – not just us – including plants and bacteria.

Why and how is it important for the immune system?

Many studies have shown a strong link between the immune system and our circadian rhythm. The circadian rhythm is thought to help ‘prime’ the host response to infectious organisms, especially during the day. A study showed that mice infected at the beginning of the sleep phase  had a lower survival rate than those infected at the start of the wake phase. 

The effectiveness of viral vaccines also depends on what time of day it is administered. This is because the receptor protein that recognizes bacterial and viral DNA is under circadian control. Men given a morning vaccination had an almost two-fold greater antibody response compared to men vaccinated in the afternoon. This makes evolutionary sense because we are more likely to be infected during the day when we are active and out and about. 

Two types of immune cells, called T-cells and lymphocytes, have been shown to migrate to our lymph nodes at night based on the circadian clock. Both cell types need to interact to produce a functional immune response so if they are present in the same place at the same time, it is more likely that they will effectively recognize and fight pathogens during our beauty sleep.

Going against Mother Nature always sounds kind of scary. However, the consequences of disrupting your natural circadian rhythm are real; disruptions to the circadian rhythm have been associated with many diseases, including metabolic disorders and cancer. There is a growing awareness that people who have a sleep pattern not aligned with the natural light-dark cycle (i.e. shift workers) have health issues, including high risk of certain types of cancer.

Viral infections can disrupt circadian rhythm

Viruses are obligate parasites – organisms that cannot complete their life-cycle without exploiting a suitable host. Thus, viruses have evolved clever ways to exploit the human immune system and hide from it. They take advantage of their host cell’s production factory for their own replication, survival and propagation. One of the ways they do this is by exploiting circadian-regulated pathways. This has been shown for various familiar viruses: Hepatitis B and C, herpes, influenza, Simian Immunodeficiency Virus (SIV), Human Immunodeficiency Virus (HIV) and unfortunately many more. 

Many viruses have intelligently evolved to attack master (regulator) circadian genes which are indirectly involved in antiviral defense mechanisms. Interestingly, some of the affected clock genes coordinate muscle function, though this doesn’t mean that you will be completely paralyzed by a viral infection! For example, scientists found that dengue virus infection in the Aedes aegypti mosquito carrier increased the amplitude of rhythmic movement in the mosquito. This was speculated to increase the carrier’s capacity to transmit the dengue virus to other hosts (humans). Other viruses have evolved ways to hijack clock proteins to activate DNA replication of viruses. Scientists have also shown that deleting a master circadian gene led to cells producing more machinery for protein production and fatty bubbles for trafficking cell products – two important steps of the viral life cycle. 

With the aforementioned consequences of interfering the circadian clock, viruses could play a role in cancer development. How likely would that be? We honestly don’t know. On a side note, let’s just take a moment to appreciate how skillful nature is in building effective killer machines.

Immune system aside, since viruses affect the circadian rhythm, can viral infections worsen sleep? Maybe, or maybe not. 70% of adult patients with HIV do experience sleep difficulties. But surprisingly, HIV viral proteins have shown to increase the production of a hormone called melatonin that helps control your sleep patterns. Doesn’t this mean you are supposed to sleep better? Exactly. There is no association of sleep quality with progression of HIV infection. However, that doesn’t mean there won’t be an association of poor sleep quality with other types of viral infections. In studies like this it is hard to distinguish whether poor sleep quality was due to a disturbed circadian rhythm or simply the result of other symptoms such as muscle inflammation and pain.

What can we learn from this?

With all the evidence of a relationship between viruses and the host circadian clock, it isn’t just about how infective the virus is or how much you have been exposed to the virus, but also the time of day when we are infected. Future antiviral therapies could potentially focus on rescuing disrupted circadian genes. More research should be done to understand how viruses interact with the molecular clockwork so we can improve treatments and manage viral infections better. 

No research has been done yet to investigate whether coronaviruses disrupt important circadian genes. But from what we have seen from previous viral-clock studies, future vaccine efficacy trials for the current coronavirus (Covid-19) outbreak will need to greatly consider the importance of the time of vaccination. 

Written by Apple Chew and edited by Ailie McWhinnie.

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