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What are 3 key mutations proving that the Delta variant of covid-19 is more contagious and deadly



One of the new variants of the coronavirus that has raised the most concern in the international scientific community is the Delta, detected in India in October 2020 and which has so far spread to at least 96 countries.

Even in some of them, such as Singapore, the United Kingdom and Portugal, it has become the dominant variant, displacing even other variants more contagious than the original virus.

Based on published data, it is known to be more transmissible than other variants, carries a higher risk of hospitalization and reinfection, and generates a slightly different symptom picture (more headache and less cough, for example).

The delta variant is estimated to be between 30% and 60% more transmissible than other variants of the coronavirus. And it can be up to 80% more contagious than the virus that emerged in Wuhan, China in December 2019.

Researchers are studying Delta’s ability to evade vaccine protection, but there is no confirmation of this hypothesis. In other words, studies so far show that vaccines are still effective against delta.

What makes this delta variant more concerning? Generally speaking, it is a set of genetic “enhancements” that facilitate the spread and invasion of the human body .

Fact that is also enhanced by external factors, such as low vaccination, or the behaviour of society without control and prevention measures, which also influences the greater transmission of these variants.

Science learned in this year and a half that Sars-CoV-2, the coronavirus that causes covid-19 disease, does not have as much capacity to mutate as the flu virus, for example.

But when new variants emerge, they can acquire”advantageous” features that make them viable in an environment of so much competition and selection to invade human bodies.

In a presentation on the delta variant to the South African government, bioinformatician Tulio de Oliveira, director of the Krisp laboratory at KwaZulu-Natal University (South Africa), listed the main characteristics of the delta variant. “It is more communicable and more likely to re-infect people who have already become ill with other strains, but there is still no clear evidence whether delta causes more serious disease or escapes the protection provided by vaccines. Oliveira also listed three groups of relevant mutations of the delta variant:

But what do each one mean and how important is it?

1. More efficient cell invasion

One of the keys to these changes, acquired by mutating, is the key that the virus has found to enter our cells. More specifically, the link between the virus spike (also known as protein S) and the ACE2 receptor, an enzyme found on the surface of our cells. This spike acts as if it were the key that opens the lock of our cell and allows the invasion of the coronavirus. Once inside, it uses the cell structure to multiply. In the case of the delta variant, there are two relevant mutations in the spike, known by the codes L452R and T478K.

But what do these numbers and letters mean? The first letter is the type of amino acid that existed before the change (L, symbol of lysine), the number corresponds to the location (452º of 1273 amino acids) and the last letter is the amino acid that entered its place (R, symbol of arginine). It must be explained that a virus is a nucleic acid (DNA or RNA) surrounded by sets of amino acids (proteins). The outer layer serves to adhere to and invade the human cell, for example, and the inner layer serves as an instruction manual to be used to produce new viruses within the invaded cell.

The surrounding amino acids can undergo three types of mutation during this virus production process: deletion (deletion), appearance (insertion), or change (substitution). These mutations do not occur for any specific reason and are often lost along the way.

But some of them are established and begin to appear from the replication of the virus. This is the case for two key delta mutations: L452R and T478K.

The change from L to R at position 452 and the change from T to K at position 478 turned out to be “advantageous” for the virus because they helped the invader to better adhere to the gateway (the ACE2 enzyme). This explains why this variant has become more transmissible.

In addition to more efficient invasion, there is a tendency that the more viruses invade cells, the more viruses will replicate, increasing the viral load.

Therefore, there will be more viruses that will be spread by coughing or sneezing, for example.

According to a study published by researchers from the Chinese Centers for Disease Control and Prevention found that a person infected with the delta variant can have up to 1,000 times more viruses in their body than someone infected with early versions of the coronavirus at the beginning of the pandemic. , at the end of 2019. This higher viral load may also be associated with greater severity of the disease, as the variant tends to affect more human respiratory cells.

2. More efficient activation and theory of the creation of coronavirus in the laboratory

When a virus seeks to invade the human cell, it is not enough that it finds a gateway and attaches itself to it: it must first be activated. In the case of Sars-CoV-2, this activation occurs through an enzyme in the human body (called furin) that cuts the coronavirus spike in two: S1 and S2. After this cut, called cleavage, one part of the spike (S1) adheres to the human cell and the other (S2) fuses its membrane with the membrane of the human cell, allowing the insertion of genetic material and initiating the production of more viruses. By cutting the spike, the enzyme causes it to open up and reveal hidden genetic sequences that help it bind more closely to cells in the human respiratory tract, for example. A mutation near this location can further alter this behavior. This is the case of the delta variant, which carries a mutation (P681R) in that region.

“ The more sensitive to human furin, the more efficient the virus spike will be . This fusion process activated by furin is mediated by the area from amino acid at position 618 to amino acid position 1273 ”, explains virologist José Eduardo Levi, research and development coordinator of the Dasa laboratory network, and researcher at the Institute of Tropical Medicine of the University of São Paulo (USP). “A mutation in this region, like P681R, makes this fusion faster. This mutation appears both in the delta and alpha variants, discovered in the United Kingdom, and in some cases in the gamma, discovered in Brazil ”, he adds.

Mutations in this region of the coronavirus are so relevant that they are at the center of two central points of the pandemic. First, this affinity for human furin is believed to have been crucial in allowing the virus to emerge from other animal species and begin infecting humans in late 2019.

Secondly, this mechanism is so efficient and atypical among the types of coronaviruses that infect humans that it has become the main argument of those who claim without evidence that Sars-CoV-2 was generated or modified in the laboratory.

“All coronaviruses that infect humans have a certain domain, a specific area that furin recognizes,” explains Levi.

“ But Sars-CoV-2 is very humanized. In other words, it is much more efficient than what has been seen in other coronaviruses , which have a reasonable recognition of furin. ” “And only Sars-CoV-2 has this mutation, this insertion of four amino acids. That is the strongest argument that this coronavirus was created in the laboratory ”. “Because so far, no intermediate coronavirus has been found that indicates that it was improving little by little.

This arrived ready to be segmented by human furin “, adds the scientist. According to the expert, the lack of this four amino acid sequence in the Sars-CoV coronavirus may explain why it caused a Sars epidemic limited to Asia in 2003, which did not become a pandemic that has spread throughout the world like Sars -CoV-2.

3. Partially escape from antibodies and vaccines

“ In learning to defend themselves, defense cells, like neutralizing antibodies, use parts of the invaders to know how to identify and fight them. When mutations occur in the coronavirus, for example, it is as if the parts of the antibodies no longer fit well with those of the invader, making it easier to escape. Therefore, the virus can at the same time mutate to more efficiently couple to the cell’s entrance gate and partially escape from the socket with neutralizing antibodies ”, explains Fernando Spilki, professor at Feevale University and coordinator of the Red Corona -Ômica, at the Ministry of Science, Technology and Innovation of Brazil .

“It is as if the virus creates pathways to escape the immune system and develops more effective forms of transmission.

All these changes were foreseen in laboratory experiments, which are capable of analyzing the influence of each exchange, insertion or deletion of these small pieces on the behavior of the coronavirus ”, he added.

In the case of the delta variant, the mutations linked to it are the T19R substitution and the 157-158del deletion. The substitution of the amino acid T (threonine) for the R (arginine) at position 19 makes it difficult for the body’s defense system to identify the invader to fight it.

In the case of coronaviruses, the N-terminal region (NTD) is considered more antigenic or immunogenic, that is, the human defense system “perceives” better and produces more antibodies against it. The spike (protein S) is the most antigenic of them, so vaccines directed at this structure are generally produced to teach the body’s defense system to identify it to fight the coronavirus as a whole. This is where mutation comes into play as a way to hamper the fight against coronavirus. Changes (deletions and substitutions) in the structure of the delta variant in an antigenic area (NTD) make it difficult for the body’s defense system to function.

“Why does it start deleting parts of its genome? You have to have a strong reason for that. Which? The human immune response, whether natural by infection or induced by vaccines ”, explains Levi. “In general, the deletion is harmful, that is, it makes the virus ineffective and ends up being eliminated . But in the case of the variants of the coronavirus, these deletions are being advantageous because they eliminate regions that provoke a very strong immune response in the host and thus manage to escape (from the human defense system) “, he adds.

So far, there is evidence that the delta variant can escape the antibodies of people who have already been infected with the beta variant (discovered in South Africa).

But there is no evidence yet that it is able to escape the immune response generated by vaccines.

It is worth remembering that none of these mutations is exclusive to one variant or another. What makes them worrying is their set. That is, at the same time they have new characteristics that make them better invade cells, be more efficient to activate and escape the defense system.

According to Levi, the context of several variants that have random mutations that are relatively similar is called evolutionary convergence. This is due, among other reasons, to the evolutionary pressure of natural selection against the most diverse forms of coronavirus in the world is practically the same: people are acquiring immunity, either from the vaccine or because they were infected with the virus. .

The same occurs with the “missing” amino acids at positions 157 and 158. In general, proteins have two ends, one called the N-terminal and the other C-terminal.

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