A Battle of Time: Biological clocks have a hand in defense against infection

by Ziqi Chen
figures by Rebecca Senft

Have you ever travelled across time zones? If the answer is yes, you might be familiar with jet lag, a condition that results from an altered internal clock. Jet lag causes symptoms such as disturbed sleep, stomach problems, and mood swings. In recent years, emerging lines of evidence show that jet lag might also affect our immune system, and our internal clock is linked to our ability to fight infection.

Jet lag is just one example of altered circadian rhythm, or biological clock, which is the intrinsic time-tracking system that syncs biological processes in our bodies with the environment, particularly external time. Two circadian rhythms are involved in an infection—that of us humans (the hosts) and that of the microbes. Microbes (viruses, bacteria, etc.) that infect us and cause diseases are called pathogens. Through evolution, hosts have adopted circadian rhythms that maximize protection against pathogens, while pathogens have adopted rhythms that help them infect the hosts and spread. How do the two rhythms interact? How does this “battle of time” affect disease outcome? By unraveling these questions, researchers are one step closer towards better timing of drugs and vaccines for maximum clinical benefit.

What makes biological clocks tick?

From microbes, to plants, to animals, virtually all life on Earth has evolved to adapt to the cycles of day and night. This adaptation manifests as biological processes and behaviors that oscillate in a 24-hour cycle. For example, plants prepare their cellular machinery to maximize nutrient synthesis (a process that requires sunlight) in the day, and animals have sleep-wake cycles. Species like bats and mice are active at night, while we humans are active in the day. The starting points of circadian rhythms are set externally by signals such as light, feeding, and temperature. Once the cycle has started, though, its progression is regulated by internal factors. In other words, external cues jump start the circadian cycle, but then the controls are taken over by the internal machinery of an organism.

In humans, circadian rhythms are regulated by a central clock circuit in the brain, and by peripheral clocks present in virtually all other organs. On a molecular level, both clocks depend on a specific set of proteins, or molecules that do much of the work inside of living cells, that are aptly called “clock proteins.” But, the two clocks receive different signals. The “central clock” begins with the sensing of light by our eyes. The cells connecting our eyes and our brain relay the signal to a brain region called the suprachiasmatic nucleus (SCN). The SCN then instructs our body to enter “day-time mode”. Conversely, when no light is sensed, our body enters “night-time mode”. In contrast, the “peripheral clock” is a term for cellular processes outside of the SCN that also track time through rhythmic oscillations. They can receive signals other than light, such as food and exercise. For instance, the liver clock is sensitive to food intake, and matches metabolism with our eating schedule. The central clock and peripheral clocks coordinate to facilitate adaption to our environment.

Figure 1: The human circadian rhythm. Our circadian rhythm is regulated by both “central clock” and “peripheral clocks” (body oscillations). The “central clock” is located in SCN in the brain and receives light signal. The “peripheral clocks” are present in various organs, and receives signals from feeding, exercise and social interactions. The “peripheral clocks” can be either autonomous or regulated by the “central clock”. The two clocks work together to regulate circadian-controlled biological processes and behaviors.

Our own circadian rhythms, though, are not the only ones ticking away inside our bodies. Pathogens, too, have biological clocks, and the interplay between these two temporal systems could have large impact on our susceptibility to infection.

Host defensive strategies to maximize protection

The evidence that circadian rhythm plays a role in infection dates back to the mid-20th century, when scientists found that in mice, time of infection affected disease severity. For example, mice infected with pneumococcus (a bacterium that can cause pneumonia) at night survived longer than those infected in the day. In mice, similar phenomena have been observed for many other pathogens, such as listeria, influenza, and herpes viruses. Most often, the immune system (responsible for defending the body against invading pathogens) responds more strongly and thus the disease symptoms are less severe when infections happen during the host’s active period (night for species such as mice and bats, and day for species such as us humans).

Circadian rhythm regulates many processes that contribute to strengthened host defenses. During the active period: (1) More defense proteins and chemicals are present to prevent pathogens from getting in; (2) The host is faster at detecting pathogens that get in, and sending out alarms to recruit immune cells; (3) Recruited immune cells work more effectively to eliminate pathogens.

The circadian clock is an “anticipatory” system—our body prepares for what is to come before the actual encounter. From this perspective, there are advantages to having stronger defenses during active period when there are higher chances of infection (e.g. through feeding for food-borne pathogens, and through social interactions). Being less vigilant at rest period also helps reduce energy expenditure, as maintaining a strong defense can take a lot of energy.

Microbe offensive strategies to maximize infection

Pathogen clocks interact with and depend on host environment and host clocks. By matching their clock with our body conditions, pathogens know to perform certain activities when its environment is most suitable. This way, the pathogen clock often facilitates its infection and transmission, counteracting host defense strategies.

One example is the malaria parasite. Upon entering our body via a mosquito bite, the malaria parasites travel to the liver and then get released into the blood. The parasites infect red blood cells, multiply, and burst the infected cell to release newly-made parasites and infect more cells. Depending on sub-species of the malaria parasites, bursting from red blood cells happens every 24, 48 or 72 hours. The replication and bursting happen during and after the host’s feeding period, which confers a survival advantage for the parasite—blood glucose levels increase after host feeding, and the glucose that is taken up by red blood cells helps support parasite replication. Indeed, when replication and bursting happen out of sync with the host’s feeding schedule, the parasite is less able to multiply and transmit.

Pathogens might also actively manipulate the host clock. For instance, Herpes virus is thought to directly alter host clock protein levels, which could lead to enhanced infection. Another example is Trypanosoma brucei, which causes “sleep sickness”, a disease characterized by disruption of the sleep cycle upon infection.

Figure 2: Role of host and pathogen biological clocks in infection. A) Host defenses are clock-controlled. During the host active period: 1) more chemicals and proteins (blue triangles) are secreted by cells (yellow) to prevent pathogens (pink) from infecting cells; 2) upon contacting pathogen (red and orange), the host cell gives out the alarm signal faster; 3) Immune cells (blue) kill the pathogens more effectively. B) Many pathogens have circadian behaviors adapted to host behaviors and environments. During host active period, pathogens have more access to the hosts and higher chances of transmission through host social interactions. C) The host clocks can affect pathogen clocks, and some pathogens can also alter host clocks to their advantage.

Many questions remain unanswered regarding how pathogen clocks work and how they interact with host clocks. In addition, there are microbes living in our body that do not cause disease. These microbes are often beneficial to us and are called “commensals”. How commensal clocks interact with our clocks is another area of active research.

Clinical outlook of circadian control

How does understanding host and pathogen clocks benefit us? Firstly, it offers new perspectives in the study of host-pathogen interactions and co-evolution; secondly, it might lead to improved disease prevention and treatment. A study in mice estimates that 43% of genes have oscillating levels throughout the day, and more than half of the 100 best-selling drugs in the US target proteins made from such genes. By giving drugs at the most suitable time (e.g. when the drug targets are most abundant), we might be able to maximize therapeutic efficacy. In the context of infection, timed vaccination might lead to stronger host immune defense, and timed treatment with anti-microbials and other drugs might attack pathogens when they are most susceptible. Furthermore, if we identify specific factors in the pathogen that are involved in circadian control, we might be able to target these factors and perturb the pathogen’s circadian rhythm. This being said, there is always concern that pathogens will eventually come up with ways to evade our manipulation, and so the fight goes on around the clock.

Ziqi Chen is a fourth-year Ph.D. student in the Biological and Biomedical Sciences program at Harvard University

Rebecca Senft is a fourth-year Program in Neuroscience PhD student at Harvard University who studies the circuitry and function of serotonin neurons in the mouse

For More Information:

To read about research findings on how circadian rhythm affects defense against pathogens, and the clinical implications, see this BBC News article.
This SITN article describes the life stages of malaria parasites, which can give context to the description in this article about malaria parasite circadian rhythms.