Welcome to The Plague Pit – issue number 15

This issue is a very special one, in that it features The Plague Pit’s first student contribution. Alfred Beadman has sent in this excellent account of the virus itself – something we should probably have had in the first issue.

Alfred is studying the sciences and maths at Winchester College and hoping to apply for medicine at a London university. His current ambitions are surgical – the precise specialty yet to be decided.

“The best parasite doesn’t kill its host”

That’s what coronavirus is: a microscopic parasite. It kills up to 5% of people it infects where flu kills a fraction of a percent.

It may seem hopeless without a degree in medicine to try to understand exactly why it is so infective and why it kills so many times more people than flu – so I’m going to explain a bit about what makes coronavirus special and how it works.

First of all, the virus is called SARS CoV-2 and it causes the disease COVID-19, it lives in a family of coronaviruses. They’re called coronaviruses because up close they have protrusions that make them look like crowns (Latin for crown is corona). To see coronaviruses, you must use an electron microscope as they are too small to see with a light microscope.

Although small to observe, they are much larger than other RNA viruses, especially with the size of their genome. SARS CoV-2 has a genome that’s 29,903 bases long. Whilst that’s not much compared to our 3,000,000,000 base pairs, typical RNA viruses only have 4,000 bases. This is one reason why coronaviruses are so special –

Inside the virus, hidden in the RNA’s code are instructions for a protein that helps them achieve their huge genome. Copying RNA makes more mistakes than DNA. Therefore, RNA viruses must have shorter genomes to avoid the accumulation of mistakes that could render the virus useless. SARS CoV-2 codes for a protein that proofreads any newly made RNA and makes sure there are no mistakes. [1] This protein is called non-structural protein 14 (NSP14) as it is the 14^th protein coded in its genome that is not included in the structure of coronavirus after it leaves its host cell.

The virus uses a range of countermeasures to combat our cells’ viral defences. For example, if one of our cells recognises that it is infected, it can make the decision to kill itself for the good of other cells, this is called apoptosis. SARS CoV-2 has evolved a way to stop this so it can continue to hijack the cell’s machinery to make more viruses. One protein, called NSP1, binds to a part of an enzyme and forces the cell into a cell survival pathway. [2] However, this protein’s main function is to prevent certain messengers (namely alpha and beta interferons) from travelling to neighbouring cells and warning them of the nearby infection.

The virus responsible for COVID-19 is very similar to that of the SARS outbreak of 2003. This is because they are both coronaviruses. However, SARS CoV-2 has a few genetic differences to SARS CoV, the virus responsible for the 2003 outbreak.

One notable difference is in the part of the virus that binds to our cells, called, spike proteins. The spike protein in SARS CoV-2 has 4 extra amino acids right where the spike protein binds to our cells [3] (receptor binding domain). After numerous studies, scientists have found out that this adaptation actually makes it harder for the virus to bind to our cells, [4] but it offers one BIG advantage…

This adaptation allows certain abundant proteases in humans to process the virus so it is primed to enter more of our cells. Without this cleavage, the spike protein could bind to our cells but not enter [4]. This is additional evidence that the virus was not engineered against humans and is probably of zoonotic origin as SARS was.

So how does COVID-19 kill? The main cause of death is Acute Respiratory Distress Syndrome, this is when your lungs, inflamed, fill up with fluid and you cannot provide oxygen to your organs. It is only present in severe cases of COVID-19 and you will need a respirator to breathe for you. The inflammation and fluid release is not just because of your body’s defence mechanisms but also because of another of the virus’s proteins and the way the virus enters cells.

SARS CoV-2 enters cells by binding to receptors that are meant to be used to inhibit vasoconstriction. The virus binds to the receptor so it cannot be used and blood pressure increases [5]. Inflammation is also promoted by the protein orf3a [6]. This protein helps speed up the process of maturing cell messengers that increase inflammation (proinflammatory cytokines). These cytokines go on to cause fluid to leak from blood vessels into the local tissue.

A few of the proteins that SARS CoV-2 codes for are still shrouded in mystery and we don’t know their function; understanding how all these proteins work along with our own molecular machines will be the key for unlocking effective treatment.

Alfred Beadman

Bibliography:

 [1] “Structural basis and functional analysis of the SARS coronavirus nsp14–nsp10 complex” Yuanyuan Ma, Lijie Wu et al. Proc Natl Acad Sci U S A, 2015 Jul 9, 10.1073/pnas.1508686112

[2] “Severe Acute Respiratory Syndrome Coronavirus nsp1 Suppresses Host Gene Expression, Including That of Type I Interferon, in Infected Cells” Krishna Narayanan, Cheng Huang et al. journal of Virology, April 11, 2008, https://doi.org/10.1128/JVI.02472-07

[3] “The proximal origin of SARS-CoV-2”Kristian G. Andersen, Andrew Rambaut  et al. Nature, 7 March 2020, https://doi.org/10.1038/s41591-020-0820-9

[4] “Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein” Alexandra C. Walls, Young-JunPark  et al.Cell, 16 April 2020,https://doi.org/10.1016/j.cell.2020.02.058

[5] “A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury” Keiji Kuba, Yumiko Imai et al. Nature Medicine, 10 July 2005, https://doi.org/10.1038/nm1267

[6] “Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC” Kam-Leung Siu, Kit-San Yuen et al. The FASEB Journal, 29 Apr 2019, https://doi.org/10.1096/fj.201802418R