Updated: Mar 17, 2020
It is hardly an understatement to say that the outbreak of the novel Coronavirus of 2019 (nCOV/ SARS-CoV2/COVID19) has become a worldwide problem since its spread around the globe started in late 2019.
There is still a lot that we do not know about COVID19, but with that said, we do have a good grasp about how the family Coronaviridae, works. What is written in this article may not entirely reflect how COVID19 behaves, but it will present how in theory the virus will behave based on observations made so far about the viral family it belongs to.
Structure and function
Coronaviruses are the second most common cause of the cold, with the most common cause being Rhinoviruses (In the family Picornaviridae, same as the Poliovirus). Coronaviruses are given their name by their appearance in an electron microscope, which looks like small suns, surrounded by a halo or a "corona". This is actually their spike proteins embedded in the viral envelope, which is actually just a cell membrane the virus has "stolen" when it buds off from a eukaryotic cell. It is mostly made out of cholesterol and phospholipids. The virus then embeds its own proteins in the envelope to suit its own purposes.
Having an envelope gives the virus certain abilities at the trade-off of losing others:
+ They are more easily spread through fluids (e.g coughing/sneezing)
+Given humid and cold conditions, they are more long lasting as an aerosol when people sneeze or cough.
+ Coronaviruses can survive in the GI tract, thanks to their Spike-glycoproteins on the envelope.
- They are sensitive to drying out e.g by heat or alcohol
- They are sensitive to soap because of their fatty envelope
The virus's genetic material is stored within a protein cover called a capsid, which has different geometrical shapes depending on what types of viruses we talk about. In the case of coronaviruses it has a helical shape (ie, it is basically an empty toilet paper roll). Inside this roll is where the genetic material is stored. For coronaviruses, it is in the form of mRNA. The mRNA strand for coronaviruses is a large one and holds a lot of genetic information.
Infection with Coronaviruses
Different coronaviruses uses different receptors on human cells to enter them. In a recent article in the Lancet, Roth and colleagues discuss comorbidities and infection with COVID19. Other scientists have concluded that both SARS and COVID19 bind to the same receptor, ACE2.
ACE(Angiotensin converting enzyme) is a family of proteins found mostly on blood vessels and epithelial cells. This enzyme family is a common drug target for medication against high blood pressure and kidney disease. Drugs commonly target ACE1, which is mostly involved with regulating blood pressure. ACE2 has a smaller role in blood pressure control. However, Roth and colleagues inquire that patientens using ACE1-inhibitors (drug class), have an increased amount of ACE2 and are therefore more susceptible to COVID19. Other medication can also affect expression of ACE2.
Anyways, all coronaviruses, and not only COVID19, follow a certain structure after infecting a cell.
1. The virus enters the cell and releases it's mRNA, which is readily translated into a viral polymerase by the cells ribosomes (RNA-dependent RNA polymerase/ "L-protein").
2. The viral polymerase produces a new , complementary strand of RNA (negative sense RNA)
3. This strand is then transcribed and translated to form several new types of mRNA for production of viral proteins and more viral genetic material (which is itself just mRNA).
4. The viral constituents are assembled to form a new viral particle in the rER, where the "budding" of the virus takes place, i.e the genetic material forces its way out into the lumen of the rER and takes a part of the rERs membrane for its envelope and enbeds it's proteins in the envelope.
5. The new virus particles are sent to the golgi apparatus and are exocytosed from the cell to infect more cells.
Symptoms in people are caused by the inflammation caused by dying cells and the immune response that follows this. The virus is spread when it mixes with mucus and secretions from the airways when it is exocytosed from cells. The virus can then be sneezed and coughed up.
How did the virus start and what makes COVID19 special?
Viruses are notoriously "sloppy" when it comes to replicating the genetic material. This gives rise to mutations over time. In humans, we have several systems to make sure mutations do not occur as they are more often dangerous. But in viruses, this can work to their advantage. Ever so often, a mutation is just right so that a virus can "jump" the species-barrier and start infecting a different species. This is likely because their viral proteins mutated just right to be able to bind to structures in humans. Scientists think this is what happened with COVID19. It is thought to originate from bats and through some genetic coincidence, its properties were just right that fateful day in December of 2019 in Wuhan, China, when Patient Zero was infected.
It is easy to speculate what makes COVID19 special, but by looking at historical cases of other Coronaviruses, like SARS and MERS, a few conclusions can be made that might be applicable to COVID19.
The common cold-causing coronaviruses prefer a temperature around 33-35 degrees Celsius, whilst the more notorious viruses have been shown to replicate at 37 degrees Celsius. This means that the "normal" coronaviruses typically infect the upper respiratory tract (nasopharynx), whilst SARS and MERS could cause systemic disease as they were less "picky" of suitable conditions for replication.
This is likely why the zoonotic coronaviruses could affect multiple organs. As noted previously, ACE2 is present on many types of cells and COVID19 and SARS can hence cause infection in multiple organs. These viruses thrives in body fluids and therefore they could enter the circulation and start affecting lungs, kidneys, liver and the gastrointestinal tract. Often times, viral pneumonia arises.
Widespread inflammation and difficulty breathing causes hypoxemia and shock (a drop in blood pressure) which starves the tissues of oxygen, resulting in multi-organ failure. This is how the viruses can become fatal. Although, it should be noted that this occurs in a very small fraction of patients. For most people, COVID19 is reported to give normal "flu-like" symptoms.
Potential cures for COVID19?
I personally believe there are 3 ways we could beat COVID19. A new drug, vaccination or by rigorous hygiene.
Hygiene is the staple for combatting any infection so it is hardly a surprise it is mentioned here. As mentioned previously, coronaviruses should in theory be vulnerable to both soap and rubbing alcohol. Use both generously.
A vaccine is of course what scientists are working on full time now. The hard thing about developing a vaccine is, aside from the rigorous clinical trials they must go through, finding a suitable structure the virus possesses (an antigen) that our body should create antibodies against (ie, finding something suitable that we inject into people). This antigen should ideally:
1. Be on the viral surface
2. Have a low tendency to mutate
3. Be a protein and not another type of macromolecule (proteins induce stronger immunological memory)
We know from other coronaviruses that antibodies directed towards the surface glycoprotein called "E2" stops the virus from entering the cell, as this structure is responsible for binding and entry into cells. Therefore, it is paramount to isolate the corresponding structure on COVID19 in our quest for developing a vaccine.
Finally, a new drug is being developed against COVID19, called Remdesivir. Remdesivir is a drug that essentially tagets the viral polymerase, which is crucial for the virus to replicate inside the cell. The drug "pretends" to be an adenosine nucleotide and confuses the viral polymerase. The polymerase inserts Remdesivir into the complementary RNA-strand, thinking it is Adenosine, but because of the drugs structure, the polymerase cannot add additional nucleotides after inserting Remdesivir. The virus genome productions halts, or at least its replication is decreased tremendously, stopping or reducing further production of the virus. Wheter it will come to see use remains to be seen, but it is nonetheless a promising candidate.
Structure of Remdesivir:
Hopefully this article brought new understanding about Coronaviruses, regarding their structure and function, pathogenesis and cures. COVID19 has around 150 000 cases at the time of writing (16th of March 2020) and is set to increase. Only by using our combined scientific knowledge and by great effort of governments, organizations and ordinary people will we be able to overcome this virus. Stay safe.
Murray's Microbiology , 8th edition, "Coronaviruses", Figure 47-1 and 47-2.
Lectures by Jorma Hinkula, Linköping University. Professor of molecular virology.
The Lancet, March 11 2020, Roth M, Karakiulakis G, Fang L, "Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?"
Harvard Health, Pneumonia: https://www.health.harvard.edu/a_to_z/pneumonia-a-to-z
Remdesivir molecular structure: https://en.wikipedia.org/wiki/Remdesivir