What Makes the New Coronavirus Able to Infect Humans?
And how can we identify the next pandemic threat?
Summary
- Modelling work that began after the SARS epidemic in 2002/3 has allowed scientists to identify the way the new coronavirus infects humans
- There are specific mutations in the current virus could potentially make it more dangerous, so it's important we look out for these
- The same approach can be used to predict which animals could carry the virus
- Citizen scientists are using these techniques to design potential treatments
Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Every year, new CoV sequences are discovered. But, there is a massive knowledge gap in the field as very little work is done to analyse these sequences after the viral DNA is made public. Therefore, we don’t know whether these other viruses have the potential to spread to humans.
Since the SARS outbreak in 2002, researchers have been studying how this virus infects humans, producing fine-scale images of how the surface of the virus binds to human cells. Researchers were able to show that the virus binds to human cell proteins called ACE2. ACE2 is an enzyme attached to the outer surface tissues of our lungs, arteries, heart, kidney, and intestines. It’s important for controlling our blood pressure, but also provides a point of entry for infection by some coronaviruses.
Once the virus binds to ACE2, the enzyme is moved inside our cells and broken down, which is thought to contribute to the lung damage we see with coronavirus infections. This cell entry allows the virus to hijack our cells’ machinery to make more of itself. The coronaviruses that cause the common cold don’t bind to this enzyme, which is why they don’t cause lower respiratory tract infections or the pneumonia we’ve been seeing.
Researchers had already figured out the structure of the protein in SARS that bound to our ACE2 proteins, so once a genome sequence of the new coronavirus became available, they were able to edit in the differences and assess how this would change the binding. Through this work, they were able to show that ACE2 is very likely the route of entry of this new virus into our cells (this was also confirmed experimentally), and they were able to comment on how strongly the virus binds to our receptors, as well as those of other animals.
The implications of this work are really cool. They would allow us to predict which other viruses could infect humans via the same route, which viruses are a few mutations away from being able to do so, and which animal hosts may be carrying human epidemic threats.
Critically, the work has shown that while the new virus is suited to binding human cells, it is not ideally suited to it. Researchers had designed an ideal SARS-CoV protein that could bind to ACE2 as strongly as possible, and through comparing this to the current virus, they were able to identify specific mutations that could make the current virus bind more tightly to human cells, potentially making it more infectious and dangerous. There was one mutation in particular that could significantly strengthen the binding of the virus’ spike protein to our cells, which the researchers encourage surveillance teams to look out for.
Figuring out the host range of the virus
The ability of the virus to bind to different proteins on the surface of host cells is one of the most important determinants of the range of hosts it can infect, and how infectious the virus is. Humans aren’t the only animals to have ACE2 enzymes, so the researchers looked at how the virus might bind to ACE2 from other animals, to assess its potential host range.
This work can facilitate surveillance of new sources of epidemics, predict species ranges for these viruses and identify potential animal reservoirs and experimental models for infection.
Based on the genome sequences we have available, it looks like the virus is most likely to have crossed over to humans from a bat. However, based on modelled binding to ACE2 from other animals, its possible the virus could also be carried by pigs, ferrets, cats, and other primates (note: experimental work later confirmed infection of cats and ferrets, but did not confirm infection of pigs). Unfortunately, the work also predicted that rats and mice would make poor laboratory models for infection, meaning we would have to seek other methods for studying this disease.
Figuring out which other viruses could infect humans
The part of the virus that binds to ACE2 can be produced relatively cheaply and easily, so one group produced the same protein from other coronaviruses that had been sampled in the past. In doing this, they were able to show that other viruses from the same family had the ability to bind to our cells in the same way.
MERS, which is also a coronavirus, infects us via binding to another human protein (DPP4). The researchers tested this protein and several others that are known to be human targets of coronaviruses and found that only the MERS family of coronaviruses could enter cells via DPP4. It looks like the viruses that they tested had only one point of entry, making designing drugs to prevent infection easier.
Citizen scientists are designing potential treatments
Foldit is a revolutionary crowdsourcing computer game enabling you to contribute to important scientific research. The game allows people to try to fold proteins based on their sequence and has released a series of challenges asking its users to design proteins that could block the binding of the virus to human cells. Promising candidates that come from the challenges are then being grown in the lab and tested to see if they work.
