COVID-19 Latest Study Shows That Circadian Rhythm Is A Regulator Of Viral Infections And Affects SARS-Cov-2 Infection And Host Immune Response
: Scientist from the Aix-Marseille University-France and Méditerranée Infection Foundation (IHU)- France in a new controversial study shows that the time of the day can affect infection with the SARS-CoV-2, as well as guide subsequent host immune response implying that circadian rhythm may well be a novel target for managing viral progression.
The study findings were published on a preprint server and are currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.09.09.290718v1
The human circadian rhythm can be described as the 24-hour internal clock in the human brain that balances cycles of alertness and sleepiness as a response to light changes in the environment. In addition to its pivotal role in regulating biological functions, the circadian rhythm has been proposed as a regulator of viral infections. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191115/
Importantly and more specifically, the time of day when the infection occurred was found to be quite important for the disease progression of several different viral diseases/agents, such as influenza, respiratory syncytial virus, and parainfluenza type 3 viruses
It should be noted that all of these are respiratory viruses like SARS-CoV-2, the causative agent of the ongoing and disruptive COVID-19 pandemic. Importantly, we are still searching for an optimal tool for improving the prognosis of infection.
Scientifically, it is known that the aforementioned rhythmicity highly relies on central and peripheral oscillators, whose activity depends on two main feedback loops governed by clock gene cascade under the regulation of the primary clock gene called Bmal1. https://pubmed.ncbi.nlm.nih.gov/28799904/
More important, the consequent knock-out of Bmal1 strikingly decreases the replication of several different viruses including Dengue or Zika. https://pubmed.ncbi.nlm.nih.gov/30670689/
Importantly, among key identified proteins that are involved in SARS-CoV-2 interaction with the host, previous studies have shown that approximately 30% of them are associated with the circadian pathway. https://pubmed.ncbi.nlm.nih.gov/32353859/
As a result the lack of evidence of whether the circadian rhythm is implicated in SARS-CoV-2 infection of human cells, the French research team from France, led by Dr Aïssatou Bailo Diallo from Aix Marseille Université and IHU-Méditerranée Infection in Marseille, decided to
tackle this research question head-on by using human monocytes.
The study team first wondered whether the infection of monocytes, which are innate immune human cells affected by COVID-19, adhere to circadian oscillations. During a 24-hour period, every three hours, total ribonucleic acid (RNA) was extracted, and the expression of Bmal1 and Clock genes has been investigated in unstimulated monocytes.
In addition, the detection of SARS-CoV-2 was performed with the use of One-Step Real-Time Quantitative Reverse Transcription PCR. Moreover, SARS-CoV-2 was initially labeled with an anti-SARS-CoV-2 antibody, followed by a secondary anti-rabbit Alexa 647 antibody.
All study images were obtained with the use of confocal microscopy. Finally, all interleukin levels were measured in cell supernatants by employing an enzyme-linked immunosorbent assay method.
Interestingly, the study revealed how SARS-CoV-2 exploits the clock pathway.
Dr Diallo told Thailand Medical News, "We demonstrate here that the time day of SARS-CoV-2 infection determines consistently viral infection/replication and host immune response. It is likely that SARS-CoV-2 exploits clock pathway for its own gain.”
The study showed that the expression of investigating genes exhibited circadian rhythm in monocytes with an acrophase (peak of the rhythm) and a bathyphase (the trough of the rhythm) at Zeitgeber Time (German name for synchronizer) 6 and 17 (i.e., ZT6 and ZT17). Basically, these two-time points denote the beginning of the active and the resting periods in human individuals.
In addition, after 48 hours, the amount of SARS-CoV-2 increased in the monocyte infected at ZT6 in comparison to ZT17. Likewise, the amount of the virus at ZT6 was linked to substantially increased release of interleukin-6, interleukin-1β, and interleukin-10 when compared to ZT17.
In basic summary, the interaction of SARS-CoV-2 with human monocytes prompted the rise of distinct cytokine patterns according to daytime, and for the first time, it was shown that cell entry and multiplication of SARS-CoV-2 in monocytes differs with the time of day.
The stud team commented, "Our findings support consideration of circadian rhythm in SARS-CoV-2 disease progression and suggest that circadian rhythm represents a novel target for managing viral progression.”
Significantly, this study also emphasizes the significance of timing of any treatment solutions administered to COVID-19 patients, since circadian rhythm was found to be implicated in the pharmacokinetics of several different drugs. https://www.nature.com/articles/s41580-020-0275-3
Several treatments have been proposed to prevent the occurrence of severe forms in Covid-19. They include passive immunization, cytokines, anti-cytokine antibody or corticoids. All these candidates affect the immune response known to oscillate during the day and their administration according to Circadian Rhythm of SARS-CoV-2.
The study team also stresses that the well-known circadian rhythm disturbance characteristic for intensive care units should never be neglected in the clinical management of patients presenting with severe forms of COVID-19.
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