That is the question we all ask ourselves. What has happened so that, in just a few weeks, we find ourselves in a situation equal to or worse than what we had during the spring lockdown. The speed of propagation surprises us and, although we do not yet have all the answers to the question, in the last few weeks very important discoveries have been made that help us understand what is happening.
Is SARS-CoV-2 more contagious than other coronaviruses?
The answer is yes. There are two other very similar coronaviruses that also cause very serious respiratory disease: SARS-CoV, which appeared in China in 2003, and MERS, which spread in the Middle East in 2012. Both had a fatality rate much higher than that of SARS-CoV-2 (35% of MERS patients died), but its infectivity was much lower. Despite initial fears, both outbreaks died out without causing the dreaded pandemic.
But, if they are so similar, why is the current coronavirus so highly contagious, while the others were not?
The answer lies in the insertion of four amino acids. Only four. A virus actually acts like a parasite that needs to get inside a cell to replicate . To enter it, it attaches itself to a molecule present on its surface (its receptor) and, once anchored, this receptor acts as a Trojan horse by internalizing itself and dragging the virus with it into the cell.
For this to happen, it is necessary for the membrane of the virus and that of the cell to fuse, and there certain enzymes (proteases) that favor this process play a key role. We might think that SARS-CoV-2 is much more infectious than its other two close relatives because it uses a different receptor or proteases. Well no. It uses the same receptor (angiotensin convertase enzyme-2, ACE-2), and also the same protease (transmembrane serine 2 protease, TMPRSS2).
So what is the difference? We return to the four amino acids that have been inserted into the spicule protein (the “crown”) of the new virus, and which is not present in the previous ones. These four amino acids (Arginine-Arginine-Alanine-Arginine, RRAR) create a new cleavage site on which a different protease can act, furin, which is very active and abundant in the lung.
For months it was suspected that this site was a key element in explaining the increased infectivity of SARS-CoV-2, but only recently have we confirmed this hypothesis. In an interesting study, a variant of SARS-CoV-2 was produced in the laboratory in which these four amino acids had been eliminated, so that the furin cleavage site no longer existed. The resulting variant had a lower ability to infect lung cells in vitro and also a lower ability to infect model animals.
Hamsters infected with the deleted variant had a very mild disease and the virus had poor replication capacity, while animals infected with the unhandled SARS-CoV-2 suffered from severe disease. Therefore, this furin cleavage site (the four inserted amino acids) confers much greater infectivity to the virus that causes COVID-19 than that exhibited by its 2003 and 2012 predecessors.
But that is not all. Very recent data have shown that, as a consequence of furin cutting, a second site is created in SARS-CoV-2, not present in its predecessors, which favors infection by interacting with a new molecule: neuropilin, which helps even more so at the entrance of the virus. A small change has caused us a big problem.
New, more infectious variants
These data explain why the virus is more infectious than the previous ones, but the progression of the disease now seems much faster than in spring. What happened?
Well, the virus has changed, and this time in a single amino acid: amino acid 614 of the spike protein, initially an aspartate, is now a glycine. This is what is called the D614G mutation. It began to be identified in Europe at the end of February, and in April most of the viruses that circulated already contained this variant that is now hegemonic on the continent. Logic indicated that this minimal change, one amino acid for another, was sufficient to confer much greater infectivity since the mutated variant had managed to completely displace the original.
It had to be demonstrated in the laboratory. And, indeed, this variant is much more efficient infecting different types of cells. The most important thing is that the animal models also support it. When hamsters were inoculated with the new variant, it was found to be much more efficient infecting cells from the nose and trachea, but not from the lung. Furthermore, when the animals were administered both simultaneously, the mutated one rapidly outgrown the original.
These experiments tell us that the new, now dominant variant is much more infective. Fortunately, it is not more virulent, since there are no differences in the ability to infect lung cells. Nor has it been established, in patients, any correlation between the new variant and the severity of the disease.
The Spanish variant
Recently a new variant has been published, now dominant in Europe. Spanish and Swiss scientists have discovered a new mutation (added to D614G), and which again results from the change of an amino acid: the Alanine 222 of the spike is replaced by a Valine (20A.EU1 mutation). It was detected in 7 Spanish and 1 Dutch samples obtained on June 20. On July 18 he was in the UK, on the 22nd in Switzerland and on the 23rd in Ireland. In New Zealand it was September 22.
Although the biological significance of this variant is not yet known, it is possible that it confers even greater infectivity on viruses because they have spread so rapidly.
How did we get to this situation
To explain it, there are elements related to the virus and others to social behavior. The current wave may be due to a variant much more infective than the spring, although not more lethal, which partially explains the tremendous speed of spread.
In this sense, it is possible that what has been lived in Spain was an advance of the calendar of the second wave that all Europe now suffers, since the new variant would have originated in this country. Most likely, a precipitous de-escalation and carefree social behavior during the summer contributed to this, so there are not only effects attributable to the virus.
Two good news, to finish. These mutations, in addition to not being more pathogenic, probably will not have any effect on the vaccines that are being developed, and which are based on the original sequence, nor on the ability to block the virus by neutralizing monoclonal antibodies that are close to be approved. It’s something.
Ignacio J. Molina Pineda de las Infantas, Professor of Immunology, Center for Biomedical Research, University of Granada
This article was originally published on The Conversation. Read the original.
