What makes coronavirus an 'ace' at invading cells? Blame its club-shaped protein spike and a molecule in the human body

In the months since the coronavirus stormed on to the world’s stage, millions have been infected and billions of other lives affected indirectly. It is thought that anywhere from a quarter to half of those infected show no symptoms.

At the other end of the spectrum, a small but significant minority have suffered very a severe case of coronavirus and died.

Representational image. Image by HenkieTenk from Pixabay.

Researchers have worked around the clock to learn more about the SARS-CoV-2. A number of vaccines and treatment options have gone into clinical trials, with the hope that they will be safe, effective, and available on a global scale soon.

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A clearer portrait of this grim killer and how it spreads is now emerging. We now have a much better sense of how the virus infects cells and tissues, and how the immune system fights back.

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When we talk about immunity, we refer to the good work done by the acquired immune system, more specifically the B cell response after infection, and the immune memory that prevents reinfection for a certain amount of time.

The good news is that the coronavirus elicits a robust immune response in most people after infection. However, a few people might not develop long-lasting antibodies which can prevent reinfection. Given the short duration that the virus has been infecting people, we don’t yet know the duration of immunity either.

But much before antibodies start to develop (around a week after symptoms show up), the coronavirus has to enter the body and find cells to infect. It also has to fight against the other defense system: innate immunity, which is always on the guard against infiltrators.

In most cases, the immune system will successfully get rid of the virus and kick-start the second line of defense: adaptive immunity.

For some people, the initial immune responses can get out of control and cause the destruction of healthy tissues. This can result in some of the worst outcomes such as severe lung damage, blood clots, multiple organ failure and death.

Doctors track lymphocyte counts in patients, because a low count early on is a warning that the immune response is abnormal and things might get worse later.

Immunity is complicated, for sure.

In the past few months, we have learned that the coronavirus is more transmissible than originally thought. The infectiousness of the virus is what ultimately makes unprecedented control measures necessary, because a relatively small number of dead out of a very large number of infected is still a large number.

In humans, coronaviruses mainly cause respiratory infections. There are four pesky, established coronaviruses that infect the nose and throat and cause minor colds. In addition, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) are caused by two coronaviruses that have jumped from other animals in recent years.

Both viruses have difficulty infecting the upper respiratory tract, but cause serious problems in the lungs.

What makes the pandemic-causing coronavirus responsible for COVID-19 so infectious and so difficult to control is that it can infect both the upper and lower airway. Early in the infection, the pandemic coronavirus infects cells in the nose and throat (which can cause disturbances in smell and taste).

This corresponds to the phase of the infection when the virus is most transmissible. In those with mild or no symptoms, this is often the extent of the infection.

In others with moderate to severe COVID-19, the virus can go deep into delicate lungs where it can cause pneumonia. From there it can attack the intestines, heart, liver, blood, kidneys and brain. This is when severe immune responses are also triggered in many vulnerable people.

What makes the coronavirus more transmissible that SARS coronavirus or MERS coronavirus? All the details of infection are not yet known, but it is believed that there are components of the spike protein that lets this virus infect a variety of different cells in different places.

The spike protein is a club-shaped protrusion that extends from round surface of the coronavirus which gives it a distinctive sun-like appearance.

The coronavirus enters cells by using its spike protein as a “key” to unlock the angiotensin converting enzyme 2 (ACE2) receptor “lock” in many cells. In order for this to happen part of the spike protein has to attach to the receptor. Now, normally the ACE2 receptor is involved in other physiological activities such as the regulation of blood pressure. But in this case, it inadvertently serves as a conduit for infection.

This is a key point that cannot be emphasized often enough. If a virus can’t find a cell receptor to bind on to and a way to get inside a cell, infection does not occur. Disease is halted.

This isn’t the first coronavirus infecting humans to exploit the ACE2 receptor. The coronavirus that causes SARS also uses the same receptor as an entry point. But the fit wasn’t as good: SARS spike protein didn’t latch on the receptor as tightly.

The part of the spike protein that determines how well it fits with the receptor is the aptly named receptor binding domain of the protein. It is estimated that the spike protein of this coronavirus latches on to the ACE2 receptor at least ten times stronger than the spike protein of SARS coronavirus.

This is one of the reasons why the virus shows up in so many different cells and in so many unexpected places.

At the same time, the receptor binding domain is grasping the receptor, another part of the spike protein fuses the membrane covering the virus with the membrane of the host cell. This step has to happen for the viral package to enter the cell. For the two membranes to fuse, the spike protein has to be split open first, and the pandemic coronavirus does this very well too.

Viruses are tricksters in that they fool hosts to do their bidding. In this case also, it’s the host machinery that is deceived into performing these tasks. Certain proteins in cells known as protease act as cleavers. When they see a patterns of amino acid building blocks of proteins that they recognize, they make cuts.

The number of steps and protease enzymes needed for the virus to fuse with the cell varies among the coronaviruses that infect humans. For example MERS has a two-step cutting process that manipulates two cellular proteases. First, an enzyme called furin recognizes a very specific arrangement on the spike protein and makes a cut. This is followed by a second cut by another protease.

Interestingly, the original SARS coronavirus wasn’t able to use the furin enzyme to infect human cells. Because this coronavirus is most closely related to the SARS coronavirus among all the viruses that infect humans, scientists were a bit puzzled to find that it had an arrangement similar to MERS coronavirus and that it could trick furin into making that first cut as well.

This coronavirus might be more transmissible because it can lose its spike protein using furin. Furin is abundant in many parts of the body.

Something similar happens with the flu. Avian influenza A runs a gamut of symptoms from mild to severe. The influenza virus isn’t a coronavirus, so it doesn’t have a spike protein, but it does have a protein that acts like a “key” in a similar manner to the receptor it recognises.

Most influenza viruses result in mild symptoms. But once in a while, strains emerge that have an arrangement that’s recognized by furin, and these cause more severe bouts of the flu.

To recap the most important points, a more snug fit by the receptor binding domain and the hijacking of host furin to cut the spike protein before entering cells contribute to making this coronavirus so infectious and deadly.

All of this recently acquired information on how this coronavirus infects cells is being used to pick drugs and treatment options to limit the damage caused by COVID-19. As I mentioned earlier, if the virus can’t enter cells, then it can’t create more copies of itself.

Neutralising antibodies that bind to the spike protein might form naturally in those who have recovered from infection to protect them from later reinfection. That same principle drives the development of monoclonal antibodies as a treatment option.

Allowing the body to form antibodies to parts of the spike protein might also be an effective strategy for a vaccine.

A research paper published in April showed that recombinant ACE2 could fool this coronavirus to latch on to it instead of to functional receptors on cells. Another approach might be to tamper with the cell’s own ACE2 receptor to slow down the virus (but messing with a functional receptor might also have unintended side effects).

Removing the cellular proteases this coronavirus uses to cut its spike protein to slow it down is another option. Because proteases are cellular enzymes, blocking them to stop a virus from getting inside the cell sometimes have other harmful effects.

Furin, in particular is is required for normal development. But drugs like camostat and nafamostat might be effective since they tamper with the second protease which makes the other cut to pandemic coronavirus spike protein: losing this protease seems to be tolerated well by cells.

Doctors are also testing drugs that lessen the raging immune response in those with severe COVID-19. There are clinical trials underway for cytokine storm blockers such as tocilizumab which blocks the IL6 receptor, dampening its effect.

Knowing how this coronavirus infects cells and elicits an abnormal immune response in COVID-19 will help the world ultimately defeat this dreadful scourge.

The author trained as a microbiologist and is now tracking the coronavirus pandemic while maintaining appropriate social distance