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. These proteins might be small, but they are mighty. For instance, some cytokines in the reproductive tract mediate the interaction between embryo and mother, enabling successful implantation and development. Conversely, other cytokines in the reproductive tract can be fatally toxic to the embryo. Cytokines work as cell signalling molecules and are incredibly important for regulating the immune response and inflammation, amongst other functions, such as regulation of stem cell differentiation.
Why does CRS occur? 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, using a lock and key mechanism, the spike protein of the virus (the key) unlocks access into the lung cell through the ACE2 receptor (the lock). The virus then injects its RNA genome into the lung cells, hijacks the protein production machinery and starts multiplying rapidly. Unfortunately, the immune system does not recognise this as an invader and the virus has time to make multiple copies of itself. Once it has reached a certain threshold, the daughter viruses burst out of the cells, killing them. At this point, there are enough virus particles for the immune system to realise that something is very wrong, and it leaps into action. Like any war, this is a violent process and the lung cells end up becoming collateral damage. This immune response results in inflammation due to the release of cytokines by the stressed cells. This manifests in patient X as a fever. There is a delicate balance to be maintained and the inflammation response is essential for several functions, including recruitment of more immune cells to the fight and the removal of 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 multi organ failure and sometimes even death.
Proteins to the rescue!
Unfortunately, once it sets in, CRS 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 a love for protein structure and function, this paper was the most exciting thing I read during self- isolation!
Most people are aware that proteins are composed of amino acids. Of the twenty amino acids that usually make up proteins, nine are hydrophobic (do not mix with water). These are usually found in, but not restricted to proteins that reside in cell or organelle membranes (membrane proteins). Protein receptors that bind to free cytokines are examples of such membrane proteins. The tool developed at MIT is essentially a protein modification method that alters cytokine receptors in a test tube to make them compatible with water. 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. The scientists selected four hydrophobic amino acids: isoleucine (I), leucine (L), valine (V) and phenylalanine (F) and replaced them with three hydrophilic (water soluble) 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 immunoglobulin G (IgG) protein, creating an antibody- like structure. These water-soluble fusion cytokine receptors were able to soak up 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 successful, this could be the answer doctors are looking for to calm the cytokine storm during Covid 19 and other diseases.
References
- 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
- 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).
Author:
Swathi Lingam is a research fellow at A*Star in Singapore, where she is developing novel cell therapy systems to treat age-related eye diseases. She had been a Ph.D. student at the University of Manchester, followed by a short post-doc at the University of Oxford before moving to Singapore. She is passionate about science communication and loves doing that through her blog “The Very Curious Biochemist”. Follow her on Twitter.
Editors:
Saurja Dasgupta is originally from Kolkata, India. He obtained his Ph.D. at the University of Chicago, where he studied the structure, function, and evolution of catalytic RNA. He is currently doing his postdoctoral research at Massachusetts General Hospital, Boston, where he is trying to understand the biochemical milieu that could have given birth to life on earth (and elsewhere) and reconstruct primitive cells. One of his scientific dreams is to observe the spontaneous emergence of Darwinian evolution in a chemical system. When not thinking about science, Saurja pursues his love for the written word through poetry and song-writing (and meditating on Leonard Cohen’s music). His other passions are trying to make science easier to understand, and fighting unreason and pseudoscientific thinking with a mixture of calm compassion and swashbuckling spirit.
Amrita Anand is in her 4th year of Ph.D. in Genetics and Genomics at the Baylor College of Medicine, Houston. She studies the reprogramming potential of certain key factors in the regeneration of mouse inner ear hair cells. She has been actively pursuing Science communication over the last three years as she enjoys bridging the gap between scientists and non-experts. As an editor, she wants to make science more accessible to the public and also hopes the hard work behind the science gets due credit.
Linkedin: https://www.linkedin.com/in/amritaaiyer/
Twitter handle: @_amritanand
Cover image- Pixabay
