As I’ve said before you can think of a virus as a secret agent trying to break into the well-guarded and very secure fortress that is its host cell. Different viruses have slight differences in the way that they go about infiltrating the fortress: some might go for the roof, some might try and sneak through the sewers and some might kick in the door, guns blazing. If you want to stop the agent from getting into the fortress, you have to mess up their method of infiltration. Extending the analogy, if we want to stop or slow down viral infections we have to mess up their ways of getting into host cells. Because of this a lot of research on nCoV-19 is going to be on inhibiting (a word scientists use when they mean ‘messing with’) the various pieces of machinery that nCoV-19 uses to infect cells.
This sidebar is going to take a more general slant and go through the ways that coronaviruses in general infect cells. There are a few subtle differences in the mechanisms used by different coronaviruses, but the overarching idea is about the same and will give us a good base to start understanding the more specific research out there. And also, because it’s fun, this sidebar is going to keep using the secret agent analogy.
So let’s pretend you’re our not-so-friendly secret agent: Virus, Corona Virus. Before being sent out into the world you’re going to be given a battery of equipment which will include four key structural proteins (if you don’t remember what a protein is, check out my other sidebar) that you’ve chosen to nickname M (membrane), E (envelope), N (nucleocapsid) and S (spike). Most of these proteins are built into your slick spy suit and other clothing so we’re not going to discuss those here. What we are going to discuss is the S protein.
Looking more closely at the S protein you notice that it is a homotrimer– which means that it’s made up of three (tri) identical (homo) pieces that are stuck together. You choose to mount it on your arm in a cool grappling gun type structure and get ready to head out on your mission- to infiltrate a nearby fortress (cell) that has just the right sort of doors (receptor).
Your S protein is your lockpick, grappling hook and hacker terminal all at once. It’s a perfect way to get past the security of the fortress, but it only works on particular fortresses. Each fortress has different sorts of doors and entryways, and your S protein only works on one type of door. Because of this, you- the virus- are limited when it comes to which fortress (type of cells) you can infect, based on which type of doors (surface receptors) that fortress uses.
Let’s say that after a bit of sleuthing you find a fortress that has the sort of doors that your spike protein can open. The only issue is that those doors are very high off the ground. The first thing you have to do in order to open the door is to attach yourself to it. You do this by firing your S protein at the door- it’s made exactly for this and sticks to the door perfectly, pulling you into position next to the door. The next step- your full infiltration into the fortress- requires that you break free from the door, but you’re still tethered to it by your spike protein. You handle this by stealing a pair of scissors from inside the fortress (this is called a protease, and coronaviruses use host cell proteases for this) and cutting the spike protein. For many coronaviruses the spike protein is cut at the spot between its S1 and S2 pieces. For ALL coronaviruses, the spike protein is cut even more at a S2′ site. After doing this, you’re free to pass through the walls of the fortress into the secure inner sanctum.
(After attaching to a cell via the spike protein coronaviruses get into the inside of the cell by fusing their membranes with the cell membrane. I’m adding that here because trying to put it into the secret agent analogy would lead to a truly terrifying mental image).
Okay, you’re in. You’re in the fortress. Now what? Your mission goes beyond infiltration- you’re here to get reinforcements. And to get reinforcements, you have to spread your message. You accomplish this by pulling out the blueprints you’ve been carrying (viral RNA) and sneaking the main manufacturing depot of the enemy fortress (the cellular ribosomes). The manufacturing depot kinda just makes anything you put into the inbox, so you drop off your blueprints and wait. In a few minutes the raw materials you need are dropped off in the outbox. Luckily your tech department is pretty smart, so those raw materials pretty easily assemble themselves into a fast, efficient photocopier (this is called the viral replication complex). Now you’re in business.
You can use this photocopier to make many more copies of the rest of the blueprints you’re carrying (your viral RNA) and then sneak those blueprint copies back into the fortress manufacturing depot. The depot, not quite understanding the horrible fate it’s resigned itself to, continues to make the items in your blueprints. These items are all pieces of more agents, reinforcements for you. As the pieces are made and assembled you’re eventually surrounded by hundreds of copies of yourself. These secret agent clones immediately arrange for transport to the fortress walls and begin to quickly exit the fortress, searching for other fortresses to infiltrate and infect. Some secret agents use their S proteins to attach the walls of this (infected) fortress to nearby (uninfected) fortresses and climb across, forming massive complexes of interconnected fortresses that are now a new manufacturing base for your team.
You sound pretty smart, huh? Now I’m going to rephrase all of that in terms of the virus again, but briefly:
Coronaviruses get into a cell by attaching to a particular cell receptor using the viral spike (S) protein. Once a coronavirus is attached to its cellular receptor it uses host cell proteases to cleave the S protein at the S1, S2 junction. The S1 fragment of the spike protein is used more for receptor recognition and the S2 fragment helps with the next bit- fusion. The viral membrane fuses with the host cell membrane and expels its genetic information into the cellular cytosol (the inside of the cell). Once the viral RNA is in the cytosol, the cellular ribosomes (manufacturing depot) use the viral RNA to make the viral replication complex, which acts as a photocopier to make many more copies of viral RNA. These many additional copies of viral RNA are used by the ribosomes to make more viral proteins and, after that, more viruses. These viruses then exit the cell and go on the lookout for more cells to infect. Often viruses can use their S proteins to connect several cells together, making a massive, multi-nucleus complex to churn out several new viruses.
For more information on how coronaviruses infect cells, check out this paper.
References:
- Fehr, A. R., & Perlman, S. (2015). Coronaviruses: An Overview of Their Replication and Pathogenesis. Coronaviruses Methods in Molecular Biology, 1–23. doi: 10.1007/978-1-4939-2438-7_1
- SIB Swiss Institute of Bioinformatics. Coronaviridae. Retrieved from https://viralzone.expasy.org/30?fbclid=IwAR20eAwldtGjA1r9U-ANL8D3X5Uwg2kvQqmB0Ip9_wFqt8cx-NQwpKxD6e0
