CALMING THE STORM: CONTROLLING CYTOKINE RAMPAGE

Crazy little thing called Covid 19

The onset of a global pandemic has meant that suddenly everyone is a virologist, immunologist or epidemiologist. People throw around phrases such as “flatten the curve” and “cytokine storm”, without really understanding what they are. I’m not an epidemiologist, so I’m not going to touch the first one. I’m not an immunologist either, but I can definitely have a go at discussing the second one. 

Storm? What storm?

Not an actual storm obviously. A cytokine storm, or cytokine release syndrome (CRS) is simply a massive and rapid release of proteins called cytokines into the blood. Why does this happen though? Let us assume that patient X is infected with SARS- CoV2, the coronavirus that causes Covid-19. The virus enters the body and travels down the throat until it reaches the lungs. There, it enters the lung cells via a door called the ACE2 receptor. Once inside, it hijacks the protein production machinery and starts rapidly multiplying. As it is a novel coronavirus, the immune system does not immediately recognise this as an invader and the virus has time to make thousands of copies of itself. Once it has reached a certain threshold, the virus bursts out of the cells, effectively killing them. At this point, there are enough virus particles for the immune system to realise that something is very wrong, and they leap into action. Like any war, this is a violent process and the lung cells end up becoming collateral damage. This immune response also results in inflammation due to cytokines that are released by the stressed cells. This manifests in patient X as a fever of 37.8°C or higher. There is a delicate balance to be maintained and the inflammation response is essential for several functions, including recruiting more immune cells to the fight and removing dead cells. Sometimes however, the immune system tends to go overboard. Sort of like that trigger-happy fighter who won’t listen to orders to stand down. When this happens, there is an uncontrolled inflammation response, leading to a large release of cytokines. These start to attack other organs in the body, resulting in multiorgan failure and eventually death. 

Proteins to the rescue!

Unfortunately, once CRS sets in, it is very difficult to control and treat. Recently however, scientists at MIT have developed a novel protein- based tool that can be used to ‘mop up’ extra cytokines.1 This has the potential to mitigate the cytokine storm and reduce consequent fatalities. As a protein biochemist with an unnatural love for protein structure and function, this was the most exciting thing to happen to me during self- isolation!

Most people are aware that proteins are composed of amino acids. Of the twenty amino acids in humans, nine are hydrophobic (incompatible with water). These are only found in proteins that reside in cell or organelle membranes (membrane proteins). Protein receptors that bind to free cytokines are examples of membrane proteins. The tool developed at MIT is essentially a protein modification method that makes the receptors water compatible. This means that they can now be deployed in the blood stream to bind to the extra cytokines floating around and prevent them from creating systemic havoc. So how does this tool work? The scientists selected four hydrophobic amino acids: isoleucine (I), leucine (L), valine (V) and phenylalanine (F) and replaced them with three hydrophilic (water compatible) amino acids, namely glutamic acid (Q), threonine (T) and tyrosine (Y)2. The resultant protein was christened a QTY- variant receptor. The QTY- receptors were fused to part (the Fc region) of an immunoglobulin G (IgG) protein, creating an antibody- like structure. These water-soluble fusion cytokine receptors were able to bind to free cytokines with extremely high specificity and affinity, hence showing promise as therapy for CRS. Before getting too excited however, it is important to note that this effect was seen in a test tube. These QTY fusion receptors need to be tested for safety and efficacy in animal model studies and effective delivery methods have to be designed. If these tests are passed, this could be answer doctors are looking for in the treatment of CRS during Covid 19 and other diseases. 

References

1.        Hao, S., Jin, D., Zhang, S. & Qing, R. QTY code-designed water-soluble Fc-fusion cytokine receptors bind to their respective ligands. QRB Discov. 1–18 (2020). doi:10.1017/qrd.2020.4

2.        Qing, R. et al. QTY code designed thermostable and water-soluble chimeric chemokine receptors with tunable ligand affinity. Proc. Natl. Acad. Sci. U. S. A. 116, 25668–25676 (2019).

Published by The Very Curious Biochemist

I am a protein biochemist by training, with a keen interest in new and fascinating science. I am passionate about communicating and discussing science and life as a scientist. As I belong to the rare species that actually enjoys writing, I thought I'd start this blog. I'm currently a postdoctoral scientist, so this really offers me an excellent distraction from the rigours of research. I hope you lovely visitors enjoy the material on offer!

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