Immune Response to Virus: Time of Day

Our immune system’s response varies over the course of 24-hours. At certain times, we may be more resilient to fighting off viruses; at other times of the day, we may be more susceptible to pathogens.

For anyone who has traveled across multiple time zones, this altered immune response won’t come as much of a surprise. How many times have you adjusted to jet lag, just to end up with a cold or not feeling well? Similarly, you are at an increased risk of getting sick when staying up late – pulling that all-nighter before finals or working the night shift once in a while.

This article covers the background information on how your circadian rhythm and timing are important in your body’s immune response in general — and the response to viruses such as COVID-19 and the flu. Do you just want to know about COVID-19? Jump ahead to that section.

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Circadian Rhythms & Immune Function

Background on Circadian Rhythm:

The term circadian comes from Latin, circa diem, meaning about a day. Humans – and actually all animals and plants – have a built-in clock system that controls bodily functions across the course of 24-hours.

The first thing that comes to mind for circadian rhythms is usually the sleep/wake cycle. Humans (and diurnal animals) are naturally awake during the day and sleep about 8 hours at night.

Over the last two decades, researchers have uncovered the genes controlling this built-in clock and discovered that many of the body’s functions happen rhythmically. For example, we don’t produce the enzymes needed to break down different foods during the night when we usually sleep. It turns out that 10 to 40% of our cellular functions are under circadian clock control.[ref]

Resetting the clock:

Our circadian rhythm isn’t exactly 24-hours, and the body uses outside signals to reset the clock each day. Sunlight is the synchronizer of the core circadian clock. The sun comes up every morning… every single day throughout the history of the earth.

In humans, the core circadian pacemaker is located in the hypothalamus, right in the mid-part of the brain. It is called the suprachiasmatic nucleus (SCN).

The signal that sets that core circadian clock is a specific wavelength of light hitting the eyes. In the retina, you have rods and cones for color and night vision. Additionally, the retina contains non-image-forming photoreceptors with melanopsin. These receptors directly signal the suprachiasmatic nucleus (SCN) to reset the circadian clock.

The melanopsin receptors are triggered or excited, by light in the blue wavelengths. Before electric lights, the only exposure that we had to light in the blue wavelengths was due to sunlight (firelight, candlelight has very little light in the blue wavelengths).

It causes a mismatch in modern times with bright electric lights and blue wavelengths at night battling our evolutionarily conserved mechanism of resetting the circadian clock. Many research studies show the impact of blue light exposure at night on both melatonin and our circadian rhythm.(article)

Peripheral Clocks:

Different tissues and organs throughout the body have their own clock mechanism. These ‘peripheral clocks’ control the rhythm of expression of genes – the creation of different cellular enzymes and proteins – in tissues such as the skin, liver, pancreas, heart, and adrenal glands.

The liver is geared up and ready to produce enzymes needed to break down food (or medicine) at the time of day that you normally eat. Your skin produces different enzymes during the day for battling UV exposure and for making vitamin D. And your vitamin D levels rise and fall in a circadian pattern as well, with a peak mid-day. One study indicates that 25-OH D levels (the commonly tested vitamin D component) can change up to 20% over a 24-hour period. (Something to keep in mind the next time you get blood work done.)[ref][ref]

The key with these peripheral clocks is that they are also affected by your core circadian pacemaker (the SCN) in the hypothalamus. The core circadian clock interacts with the peripheral circadian clocks – and this whole system needs to be in sync for optimal wellness.

For example, the adrenal glands release glucocorticoids, e.g., cortisol, in a rhythm that is (ideally) in sync with the body’s core circadian rhythm. The hypothalamus, where the suprachiasmatic nucleus is located, also directly controls the rhythm of the glucocorticoids. The HPA axis – hypothalamus-pituitary-adrenals axis – receives input directly from the suprachiasmatic nucleus, which receives input from the sun’s natural light/dark cycle.[ref][ref]

Why am I using the HPA axis as an example here? Because the HPA axis is also very important in the body’s immune response…

Circadian rhythm of the immune system:

Key fighters in your body’s defense against pathogens include macrophages and lymphocytes. Macrophages are large white blood cells that patrol and engulf foreign pathogens, cellular debris, and cancer cells. They are found throughout the body. Lymphocytes, which are found in the lymph, are another type of white blood cell that includes T-cells and B-cells.

B-cells are made in the bone marrow, and macrophages are also formed from bone marrow stem cells.

Researchers have found an innate circadian rhythm to the production of macrophages, B-cells, and T-cells. White blood cells are released from the bone marrow at the beginning of the rest phase (night time for humans). This release leads to a peak serum circulation for these immune cells in the rest period.[ref] During the day, these immune cells then migrate into the body’s tissues, where they will do their job, defending against pathogens as well as normal cellular cleanup.[ref]

Cortisol levels, as well as inflammatory cytokines, peak during the beginning of the active phase (first thing in the morning).[ref]

You can see where I’m going here — the overnight period of rest (aka sleep) is vital for your body’s immune function the next day.

Not only is there a rhythm to the production of new white blood cells, but within the cells, there is also a circadian rhythm. T-cells, a type of white blood cell produced in the thymus, have a circadian rhythm within the cell. These oscillations are controlled in part by BMAL1, a core circadian clock gene.[ref] Macrophages also exhibit their own internal clock, which affects the production of cytokines in the cells.[ref]

So basically, there is a rhythm to when there are more circulating white blood cells in the body — plus, there is a rhythm within the cells as to when they have maximum cytokine production.

Let’s take herpes as an example…

That is one headline that I never thought I would write :-)

Animal studies show that time of day matters a lot in both herpes and flu viral replication. The mice that were infected just before the rest phase (just before mouse bedtime ;-) had a 10-fold greater viral replication than the mice that were infected at the start of their active phase. Moreover, in mice with the BMAL1 (core circadian clock) gene knocked out, the mice had higher viral replication no matter what time they were infected with either herpes simplex 1 or the flu.[ref]

A cell study showed that PER2 helps to counteract hepatitis C viral replication. PER2 is a core circadian gene that is highly expressed at night in humans.[ref]

Airway response to viruses:

In healthy people, there is a circadian rhythm to pulmonary function. Research shows that people’s lungs work better during the day (best around noon), and function is at the lowest in the wee hours of the morning (usually around 4 am).[ref][ref]

In a viral model of acute airway disease, animal studies show that circadian rhythm is also important. Researchers gave mice jet lag (messed with their circadian rhythm by changing the lighting) and found that the mice had increased susceptibility to viral bronchitis and increased virus replication. The same study showed that deleting the BMAL1 gene (core clock gene) also caused increased susceptibility to airway problems due to viruses.[ref]

To sum this up – a circadian rhythm that is out of sync, such as due to traveling across time zones or suddenly staying up several hours later than normal, causes a greater susceptibility and worsened response to a virus that causes bronchitis. It is thought that this is a similar mechanism to the time-of-day differences in asthma and COPD problems.

Circadian changes in smokers and COPD:

Patients with COPD (chronic obstructive pulmonary disease, emphysema) are at a much higher risk of problems with the flu, rhinovirus, RSV, and coronavirus. Research shows that 50-70% of acute problems (i.e., go to the doctor/hospital type of problems) in COPD are due to viral infections. The circadian decrease in lung capacity (FVC) that happens in the early morning hours coincides with emergency room visits for people with COPD.[ref]

Researchers modeled COPD in mice using chronic cigarette smoke exposure. Then they exposed the mice to influenza A. Not surprisingly, the mice with chronic cigarette exposure had a worse response to the flu than the control mice that were not smokers. When the mice were exposed to the flu, the non-smoker mice had somewhat altered circadian rhythm (active vs rest cycle), but the cigarette smoke-exposed mice had a significant alteration to their activity vs. rest cycle. In fact, they were just as active during the day as they were at night. (mice are nocturnal…) The researchers found that the core circadian rhythm gene expression was altered in the lungs of mice exposed to the flu and that the changes in gene expression were much greater in the cigarette smoke-exposed mice.[ref]

You may be thinking that vaping is the answer here… It turns out that e-cigarettes also alter the core circadian clock genes in the lungs.[ref]

What happens to the immune system when you work the night shift?

A study (in humans) looked at the rhythm of immune cell production and the rhythm of cytokines (IL-6, TNF-alpha, and IL-IB) for the study participants during a normal day-oriented schedule and then after three days of working the night shift. There were two peaks for the normal day-oriented schedule: a peak in the night-time production of the cytokines and another peak in the day due to a higher proportion of immune cells in the tissues.

When the study participants underwent three days of having a night-oriented schedule (i.e., working the night shift), the cytokine production peak was partly shifted, but the peak in the proportion of immune cells didn’t shift. So part of the immune rhythm shifted to the new schedule – but part of it didn’t. The study concludes, “This led to a desynchronization of rhythmic immune parameters, which might contribute to the increased risk for infection, autoimmune diseases, cardiovascular and metabolic disorders, and cancer reported in shift workers.”[ref]

Parasites and viruses that alter our circadian system:

It isn’t just a one-way street here where the human circadian rhythm is the only thing that matters in fighting off pathogens. It goes both ways — some pathogens can alter the host’s circadian rhythm and thus cause a worsening of the disease.

Sleeping sickness is a tropical disease that more than 10,000 people per year will contract in sub-Saharan Africa. It is caused by the parasite Trypanosoma brucei. This truly terrible disease is called “African sleeping sickness” because the parasite causes people to have altered sleep/wake cycles. Researchers in 2018 found that the parasite actually disrupts the body’s normal circadian rhythm. It causes altered sleep/wake cycles and body temperature cycles by shortening the period of the core circadian clock.[ref]

Studies also show that viruses such as herpes simplex virus 1affect the transcription of different genes, including the core circadian genes, CLOCK, and BMAL1.[ref]

A study of canine coronavirus (not the same strain as COVID-19) showed that the viral infection caused changes to sirtuin expression. Sirtuins, specifically SIRT1, can act within the nucleus to turn on and off other genes. SIRT1 is important in cell defense and the resistance to cell death (apoptosis). SIRT1 is an NAD+ dependent protein.[ref] (Read more about SIRT1 and NAD+)

Melatonin and the Immune System:

Melatonin is a hormone produced in large quantities by the pineal gland at night. Melatonin levels rise in the evening hours, peak at night, and then are suppressed during the daytime by exposure to blue light. In addition to being important for circadian rhythm, melatonin is also produced in small amounts in cells throughout the body all day. It acts as an intracellular antioxidant and also as an immunomodulator.

Melatonin from the pineal gland is vital to the immune system – and is also affected by the immune system. It is a two-way street. Studies have shown interferon-gamma to increase melatonin production, and other immune system signals can suppress melatonin. Research studies on sepsis show that melatonin may be beneficial for reducing excessive cytokine production and restoring mitochondrial function. Many animal studies show that melatonin enhances immune function prior to stimulation, but it may also tamp down an excessive immune response.[ref][ref][ref]

In other words, melatonin is needed before getting sick to keep your immune system up and running well, and once you are sick, melatonin may keep your immune system functioning at the right level.

Melatonin as an antiviral:
Melatonin has been shown in viral infection to reduce mortality and delay disease onset in infected animals. In animal studies using stressed-out mice given West Nile virus, melatonin before infection and continued ten days after infection reduced mortality and the virulence of the disease. Melatonin was proposed in research studies as being helpful for the Ebola virus.[ref][ref][ref]

Unfortunately, melatonin production from the pineal gland declines with aging as the pineal gland calcifies. The decreasing melatonin levels with age are thought to be one of the causes of declining health in old age.[ref]

What does this mean for COVID-19 and the seasonal flu?

Being generally more susceptible to viruses at night may have you re-thinking your plans to go out in crowded bars or concerts late at night during flu season. If you think about it, prior to electric lights, people were more likely to gather in crowds – and thus need their immune system on high alert – during daylight hours. It makes sense that our immune system would ‘restock’ and produce more white blood cells overnight when people are normally sleeping and not interacting and spreading germs.

The declining melatonin levels with age may contribute to the susceptibility of older people to pathogens, including the season flu viruses and COVID-19. (Melatonin isn’t the only part of the immune system that changes with age, of course, but it does seem to play a big role in overall immune function.)

If you do get sick with either the flu or COVID-19 and need hospitalization, the constant lights and noises in hospitals can be really hard on your circadian rhythm. You may want to have a sleep mask and earplugs on hand.

The alterations to circadian rhythm functions in the lungs from cigarette smoke and vaping may increase the risk for a more severe respiratory infection. While most of us know that smoking isn’t good, the changes in clock genes due to vaping may be pretty important here as well.[ref][ref]

As you get older, NAD+ levels decline. While there is still a lot of research to be done on this topic, the interaction between NAD+, SIRT1, and circadian rhythm may be important in preventing illness, especially respiratory illnesses. This research paper has a good overview of how NAD+ and SIRT1 interact with the circadian system in airway diseases. (Genetic Lifehacks article on boosting NAD+)

Getting specific for COVID-19:

A new study, published on March 16, 2020, investigated the pathways utilized by the coronavirus that causes COVID-19 and cross-referenced this with FDA approved drugs. One of the drugs suggested by this pathway analysis is melatonin. From the study: “The antioxidant effect of melatonin makes it a putative candidate drug to relieve patients’ clinical symptoms in antiviral treatment, even though melatonin cannot eradicate or even curb the viral replication or transcription^61,62. In addition, the application of melatonin may prolong patients’ survival time, which may provide a chance for patients’ immune systems to recover and eventually eradicate the virus. As shown in Fig. 5e, melatonin indirectly targets several HCoV cellular targets, including ACE2, BCL2L1, JUN, and IKBKB.”[ref]

Animal studies on viruses show that melatonin before and during viral infection may help. You can boost your own production of melatonin by blocking blue light at night. Wearing blue-light-blocking glasses increased melatonin production by 50% within a week.[ref] Bright light during the day, such as going outside, increases melatonin production at night.[ref]

Melatonin production decreases with age due to calcification of the pineal gland. Depending on your age, you may want to investigate whether supplemental melatonin is right for you. If you go the supplement route, look for time-release melatonin to better mimic the natural production of melatonin. The immediate-release formulas are cleared from your body rather quickly.

Timing of Vaccinations:

It makes sense that our immune system’s circadian rhythm can impact the effectiveness of vaccines. A vaccine gives a small amount of a pathogen so that your body will mount an immune response and then remember that pathogen.

A study in the UK looked at the timing of vaccines for the annual flu vaccine in adults over age 65. People getting the H1N1 vaccine had a significantly greater antibody response if they were vaccinated in the morning vs. the afternoon. But that same study showed that the H3N2 vaccine didn’t have a response difference between morning and afternoon vaccines.[ref]

A lot more research needs to be done on this topic, but it may turn out that there are certain times of the day that are better for getting your seasonal flu vaccine – or for getting your coronavirus vaccine next year.

Conclusion:

Keeping your circadian rhythm on track is important for your ability to fight off pathogens. Burning your candle at both ends or jet lag from travel leaves you more susceptible to viral and bacterial infections.

Is sleeping well, blocking blue light at night, and getting sunlight during the day a magic pill to prevent all diseases? Of course not. But when your circadian rhythm is out of sync, you are going to be more susceptible than you would be otherwise.

Circadian Rhythm and Your Immune Response to Viruses