By Lingyi Wang
The Earth’s self-rotation around its axis generates rhythmic day/night cycles and a circadian rhythm of 24 hours, forming the concept of a ‘day’. Virtually all organisms have evolved endogenous timekeeping systems, namely the circadian clock, to help adapt to this day/night oscillation by coordinating biological processes and behaviours in a daily rhythmic manner (Mazzoccoli et al., 2020). For example, many flowers open during the day when most pollinators are active and close at night to minimize potential damage to pollen and excessive energy consumption (Doorn & Meeteren, 2003). Similarly, animals have sleep-wake cycles at regular times each day; diurnal species like humans are active during the day, while nocturnal animals such as mice are active in the night. Conducting biological activities within such rhythms helps organisms to anticipate environmental changes and efficiently use time and energy, which offers evolutionary benefits and maximises survival chances under strong selective pressures (Scheiermann , Kunisaki & Frenette, 2013; Martinez-Bekker & Helm, 2015).
On a cellular level, many processes such as cell regeneration, DNA damage-repair and cellular metabolism are associated with the circadian rhythm (Zhuang et al., 2017). It has recently been shown that the expression of over 80% of protein coding genes exhibits daily rhythms (Mure et al., 2019). Given such importance, circadian rhythms are closely associated with the wellbeing of individual organisms. In humans, certain activities that disrupt the circadian rhythm, such as jet lag and shift work, have been linked with various health issues including increased risk of cancer and higher susceptibility to pathogen-associated diseases (Borrmann, McKeating & Zhuang, 2020; Khan et al., 2018).
For viral infection, mounting evidence has shown that the host-virus interactions exhibit ‘time of day’ difference, and circadian rhythms can significantly impact disease progression. Recently, Edgar and colleagues have reported that viral replication was 10 times higher in the infection of wild type mice with Herpes virus in the morning (at the start of mice resting phase) than during the night (at the start of active phase). However, there was not such a difference in mutant mice with disabled circadian clocks (Edgar et al., 2016). Similar cases were also observed in other mice models with vesicular stomatitis virus, in which the mortality rate was 55% higher when the infection occurred at the beginning of the rest phase than the beginning of the active phase (Gagnidze et al., 2016). Moreover, clinical research by Zhuang et al. has shown that the risk of hepatitis C virus reinfection was higher when the liver transplantation operation was conducted in the morning than in the afternoon (Zhuang et al., 2018). Therefore, considering that the virus relies on the host’s cellular machinery and resources to replicate, and the host can anticipate potential risks through daily biological rhythms, a viral infection can be described as ‘a battle around the clock’. The host and virus compete with each other to maximize their own survival, a process heavily dictated by time (Borrmann, McKeating & Zhuang, 2020).
In mammals, circadian rhythms are regulated by two types of biological clocks: a central master clock located in the suprachiasmatic nuclei (SCN) in the brain’s hypothalamus region and peripheral clocks found in every tissue (Scheiermann, Kunisaki & Frenette, 2013; Zhuang et al., 2017). Despite the circadian clock being autonomous (as it maintains oscillations after changes in time-specific external cues) (Purves et al., 2001), accurate synchronization with the surrounding environment is achieved through various external stimuli. The SCN receives light signals from the retina to match its day-night modes with the solar day. These peripheral clock sensing signals can be food intake, time spent exercising, body temperature and more (Partch, Green & Takahashi, 2014). The molecular mechanism of the circadian rhythm is achieved via a complex transcriptional/translational feedback loop consisting of a series of clock proteins. Among them, BMAL1 and CLOCK act as core activators, while PER and CRY have roles as core repressors (Curtis et al., 2014). The two types of clocks are integrated through coordination of the peripheral clocks via nerve systems and hormones such as melatonin and glucocorticoids (Astiz, Heyde & Oster, 2019).
From the host’s side in the battle against viral infection, circadian rhythms help strengthen the immune response during the host’s active period, where there is a greater chance that the host encounters viral pathogens. When the host is active, the immune system’s ability in detecting and eliminating pathogens is enhanced with more immune cells monitoring and defending against invaders. Recently,it was demonstrated that the amount of lymphocytes in the lymph nodes is at a peak at the beginning of the active phase of mice (during the night). However, the molecular mechanisms for circadian rhythm regulation and generation of an immune response is still to be established (Sheiermann et al., 2018).
On the other hand, the virus has also evolved to utilise the circadian clock to maximise its replication and spread in the host. A review paper by Nicoll et al. has described that herpes simplex virus is able to reprogramme the host circadian rhythm by altering the expression level of the clock activator, BMAL1, making the rhythmic gene replication and translation in the host favour its own progression (Nicoll et al., 2012). Another example in virus modulation of the host circadian rhythm is indirectly seen through the hormone and external stimuli reception pathways. Experiments using in vitro cell models and clinical studies in HIV patients have shown that HIV virus uses its viral protein, Tat, to perturb the light reception and melatonin hormone pathways to influence the host circadian clock, giving it an advantage against host immune responses (Clark et al. 2005; Wang et al. 2014).
In recent years, many researchers have begun to study the interplay between circadian rhythms and viral infection. Better understanding of this relationship could help improve the current treatment strategies and find new drug targets. One current example is the theory that vaccination in the morning can produce more viral antibodies and a longer lasting immune response (Kirby, 2016). This has implications in the fight against the SARS-CoV-2 virus, as mapping of the viral interactome has found 66 viral proteins that could be potential druggable targets – and the expression of 30% of them is regulated by circadian rhythms (Gordon et al., 2020). Clinical applications such as this have brought much interest into the study of circadian rhythms, and the associations with viral pathogenicity have grown many new avenues of future exploration.
Astiz M. Heyde I. & Oster H. (2019) Mechanisms of Communication in the Mammalian Circadina Timing System. Int J. Mol. Sci. 20, 343.
Borrmann H., McKeating J. A. & Zhuang X. (2020) The Circadian Clock and Viral Infection. J. Biol. Rhythms. DOI: 10.1177/0748730420967768.
Clark JP III, Sampair CS, Kofuji P, Nath A, and Ding JM (2005) HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway. Am J Physiol Regul Integr Comp Physiol 289:R656-R662.
Curtis A. M. Bellet M.M. Sassone-Corsi P. et al. (2014) Circadian Clock Proteins and Immunity. Immunity. 40(20: 178-186Doorn W. G. V. & Meeteren U. V. (2003) Flower Opening and Closure: a Review. J. Environ. Bot. 54 (389): 1801-1812.
Edgar R. S., Stangherlin A., Nagy A. D. et al. (2016) Cell Autonomous Regulation of Herpes and Influenza Virus Infection by the Circadian Clock. PNAS. (36) 10085-10090
Gagnidze K, Hajdarovic KH, Moskalenko M, Karatsoreos IN, McEwen BS, Bulloch K (2016) Nuclear receptor REVERBalpha mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis. Proc Natl Acad Sci U S A 113:5730–5735
Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O’Meara MJ, Rezelj VV, Guo JZ, Swaney DL, et al. (2020) A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583: 459-468.
Khan S, Duan P., Yao L. et al. (2018) Shiftwork-Mediated Disruption of Circadian Rhythms and Sleep Homeostasis Cause Serious Health Problems. Int J Genomics. 2018: 8576890. doi: 10.1155/2018/8576890
Kirby T (2016) Influenza vaccination in the morning improves response. Lancet Respir Med. https://doi.org/10.1016/S2213- 2600(16)30100-X
Martinez-Bakker M. & Helm B. (2015) The Influence of Biological Rhythms on Host-parasite Interactions. Trend Ecol. Evol. 30(6): 314-326.
Mazzoccoli G, Vinciguerra M., Carbone A et al. (2020) The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship Between Biological Time and Host-Virus Interaction. Pathogens. 9, 83.
Mure L. S., Le H. D. Benegiamo G. et al. (2018) Diurnal Transcirptome Atals of a Primate Across Major Neural and Peripheral Tissues. Science 359(6381): eaao0318.
Nicoll MP, Proenca JT, and Efstathiou S (2012) The molecular basis of herpes simplex virus latency. FEMS Microbiol Rev 36:684-705.
Sheiermann C. Gibbs J., Ince L. et al. (2018) Clocking in to Immunity Nat Rev. Immunol. 18: 423-437.
Scheiermann C., Kunisaki Y. & Frenette P. S. (2013) Circadian Control of the Immune System Nature. 13: 190-193
Partch C. L., Green C.B. & Takahashi J. S. (2014) Molecular Architecture of the Mammalian Circadian Clock. Trends Cell Biol. 24 (2) 90-99.
Wang T, Jiang Z, Hou W, Li Z, Cheng S, Green LA, Wang Y, Wen X, Cai L, Clauss M, et al. (2014) HIV Tat protein affects circadian rhythmicity by interfering with the circadian system. HIV Med 15:565-570
Zhuang X., Bambhatla S. B., Lai A.G. et al. (2017) Interplay Between Circadian Clock and Viral Infection. J Mol Med (2017) 95: 1293-1289.
Zhuang X, Lai AG, McKeating JA, Rowe I, and Balfe P (2018) Daytime variation in hepatitis C virus replication kinetics following liver transplant. Wellcome Open Res 3:96.