Thursday, December 8, 2016

It’s Time for Infections: How Viruses and Circadian Rhythms Interact

Have you ever wondered how time works? Now I don’t mean the societal creation of time that lets me know I am writing this post at 1:00 am, I mean biological time.  For example, how does my body know to make certain proteins or how does it know when make me tired for sleep? In other words, have you ever thought about the existence of circadian rhythms in humans. In a recent paper in Proceedings of the National Academy of Sciences titled, Cell Autonomous Regulation of Herpes and Influenza Virus Infection by the Circadian Clock by Rachel Edgar et al., (1) the authors do just this in terms of viruses. They investigate how the natural cycling and timing of biological processes in your body can influence the interaction and effects of virus.

Before we enter into more detail about what the paper demonstrates, I first wanted to briefly talk about what a circadian clock is and why they are so important. A circadian clock in its simplest form is a twenty-four hour cycle during which our genes vary expression level and transcriptional activity to coordinated our complete physiology. In a metaphoric sense, circadian clocks are like a symphony. In a symphony, there are all the different sections playing their own special music. The individual music is fine but when you put them together you can create a beautiful work of art. This is the clocks. They are what brings each individual body process together to make us the humans we are. They are also not to be taken lightly as they have been linked to overall fitness, many aspects of human health and disease such as the sleep/wake cycle, and many immune functions. (2,3) Thus, the disruption of these clocks can be disastrous. 

The authors of this paper realized the essential nature of these processes so they set out to understand how the clock can affect viral replication, viral dissemination and most importantly how the viruses affect the clocks. For all of their research they looked at the clock gene transcription factor Bmal1 and its mRNA levels as the representation of the circadian cycling in mouse and cell culture experiments.  They then complete a myriad of bioluminescent experiments to understand the change in expression level activity (a luciferase assay) and the localization of the infected cells. It is a relatively simple paper in this sense as the authors only use a luciferase assay under different experimental conditions to collect all of their data. 

They first hypothesize that the time of day when the infection occurred would influence the viral replication and found this to be true. Amazingly, mice that were infected with herpesvirus at the onset of resting phase (the beginning of the day) exhibited a 10-fold higher viral replication then mice infected just before their active phase (10 hours later, right before the night). (1)  Bmal1 transcription activity cycles so that during the day it is not active but as night approach transcription and translation begin. This is scene below in Figure 1A from the paper:

They then found that acute infections were enhanced in arrhythmic mice with Bmal1 knocked-down and that the spread of infection was greater spatial. Overall, they conclude that the entire kinetic profile of infection depends on the circadian phase that the virus encounters.

The most influential finding of the paper is that the virus is able to alter the expression levels of the clock genes to benefit its own functioning. In figure 5 D, seen below, the authors demonstrate that the infection of Herpes Simplex Virus 1 cause the up regulation of Bmal1 for a longer period of time. The paper also concludes that all these effects occur with Influenza A to demonstrate that this is not only herpes viruses.

After all of their findings, I just have one major critique that leads to what I believe should be the next step after this experiment. Looking at the Bmal1 expression was a great way to start but circadian rhythms are influenced by a lot more genes than just this one. Thus, I would propose that they do the exact same experiments but look for expression of other clock genes. There are also a lot of downstream interactions that occur with the products of Bmal1 so an investigation into how these might change could also even up providing so key information on how the system works as a whole.

Now these findings are all very interesting but why do we care? Well first off, it is important to understand how viruses function so we can work on ways to treat them. For example, by knowing that the herpesvirus highjacks the circadian clock gene Bmal1 we could work on developing a drug that would inhibit this interaction. This would not be a cure for anything but it would help to minimize the amount of virus so that your immune system could possibly be more effective in clear the virus and inhibiting latency. The other really interesting possibility is creative a drug that keeps our circadian rhythms the exact same.  In the paper they demonstrate that arrhythmic cycling increase infection and it is known that Bmal1 expression undergoes seasonal variation to be lowest in the winter months.(4) This is possibly why Influenza and other virus are known to have more infection during the winter, so by making a daily supplement that regulates your Bmal1 expression levels you could stave off more infections. 
In the end this paper found some novel findings to demonstrate how research that is done in today’s world is amazing at find molecular interactions but it is also very important to look at the whole system. Isolated findings on how viruses function are great but it isn’t until you are able to understand the role that finding plays in the larger picture that we can move forward with our understanding of the natural world.

Source Paper:
1.Edgar, Rachel S. et al. "Cell Autonomous Regulation Of Herpes And Influenza Virus Infection By The Circadian Clock". Proceedings of the National Academy of Sciences 113.36 (2016): 10085-10090. Web.

Additional Research:
2. Scheiermann C, Kunisaki Y, Frenette PS (2013) Circadian control of the immune system. Nat Rev Immunol 13(3):190–198.
3.Curtis AM, Bellet MM, Sassone-Corsi P, O’Neill LA (2014) Circadian clock proteins and immunity. Immunity 40(2):178–186.
4.Dowell SF (2001) Seasonal variation in host susceptibility and cycles of certain infectious diseases. Emerg Infect Dis 7(3):369–374
All Figures are from source paper.

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