The 4 keys that explain Ómicron's anatomy and its high contagion power

The peak that Argentina recorded in mid-January in the middle of the third wave of coronavirus and with more than 140,000 cases in just 24 hours was no accident. This was the time when all infections responded to the latest variant of the Ómicron coronavirus, discovered in November 2021 in South Africa and which is probably the fastest spreading virus in the history of the humanity, according to science.

Experts have studied that a person with the measles virus could infect 15 others in 12 days. But when Ómicron suddenly arrived last summer, he jumped from person to person so quickly that a single case could lead to six more after four days, 36 cases after eight days, and 216 cases after 12 days. At the end of February, the variant accounted for almost all new COVID infections in the world.

When the Alpha variant was detected in November 2020, scientists knew little about how its few mutations would affect its behavior. Now, after more than a year of knowledge and data, researchers have been able to link some of Ómicron's 50 or more mutations to the mechanisms that have helped it to spread so quickly and effectively. This research process usually takes much longer, said Dr. Sriram Subramaniam, a biochemist at the University of British Columbia. “But we've been analyzing these variants for a year, so we were prepared,” he added.

According to the expert, Ómicron harbors twice as many mutations as other variants of interest, and its sublineage BA.2 may have even more. There are 13 mutations in the Omicron tip protein that are rarely seen among other variants. Those changes in his anatomy gave him amazing new abilities. “If Delta is the brute force Hulk variant, think of Ómicron as Flash, masked and evil fast,” he insisted.

A study published by Scientific American explores four ways in which the variant has physically changed. Three of these alterations helped this version of the virus evade our immune system and become more infectious, while the fourth could have led to a milder disease.

1-Use of a disguise: What made Ómicron so transmissible, as most of the evidence indicates, is a unique and powerful mechanism among the variants. Omicron had an unparalleled ability to hide from the immune system, as if it were a disguise. During infection, clusters of fist-shaped amino acids above the coronavirus peak called receptor binding domains (RBDs) attach to a protein on the outside of some human cells: the ACE2 receptor. To avoid this attachment, the immune system creates antibodies (Y-shaped proteins induced by a previous infection or vaccination) that recognize an RBD and attach to it like a velcro, hindering the virus from linking to ACE2.

In earlier variants, one, two or perhaps three amino acids were mutated in the RBDs, altering each RBD sufficiently to prevent some but not all antibodies from recognizing it. But Ómicron harbored 15 RBD mutations, many at major antibody binding sites, forming an elaborate disguise to avoid many more antibodies. It was as if the virus had put on a latex mask Mission: Impossible to change his face. “There are so many mutations and so many new ones,” says Matthew McCallum, a biochemist at the University of Washington.

In an analysis published in the journal Science, McCallum, with his head of laboratory David Veesler and his colleagues, showed a consequence of this dramatic transformation: only one of eight antibody treatments for COVID used in hospitals, which are based on natural antibodies, is still effectively bound to RBDs. Other research has shown that mutations in RBDs and a second site called the N-terminal domain allow the virus to avoid antibodies acquired by vaccination or infection. Thanks to Ómicron's convincing costume, the variant found no brakes and spread at lightning speed. The vaccines, however, still prevented serious illnesses, especially with booster injections.

2-Stabilization: When Ómicron drastically altered its beak to hide from the immune system, those changes eliminated some chemical residues that the same peak needed to bind to ACE2. But other mutations compensated: RBDs formed new chemical bridges to effectively bind to the protein, according to another study in Science. “It clearly lost some important residues for the union, but it made up for them with other interactions,” said Subramaniam, who was the lead author of the article.

The spike protein also became more resistant. In other variants, two subunits within the spike, S1 and S2, are slightly connected. This allows them to divide quickly so that the beak can be buried in a human cell when the virus finds one. The disadvantage of this delicate arrangement, however, is that many peaks break prematurely, before approaching a cell. Once separated, the spikes can no longer help the virus adhere.

Mutations in Ómicron resulted in thin molecular bridges that hold the subunits together better, according to several studies. One was published in the Journal of Medical Virology and the others were published as preliminary articles that have not yet been formally reviewed by other scientists. “This virus has really protected itself from premature activation,” said Shan-Lu Liu, author of one of the articles and director of the Emerging Viruses and Pathogens program at Ohio State University. “When the virus is in the right place at the right time, it can activate and enter the cell, but not before that.”

3-Find the side door: In the previous variants, there was one constant: the virus relies on a protein on the surface of human cells called TMPRSS2 (pronounced “tempres dos”) to help it cross the cell membrane. But Ómicron didn't use TMPRSS2. He took a completely different route to the cell. Instead of breaking down the front door, Ómicron slipped over the side. While other variants require the ACE2 and TMPRSS2 proteins to inject their genome into a cell, Ómicron bound only to ACE2. It was then wrapped in a hollow bubble called the endosome. The bubble slid into the cell, where the virus burst and began to take control.

Scientists speculate that Ómicron gained two possible advantages in this way. First, many cells don't have TMPRSS2 on their outside, so if the virus doesn't need the surface protein, it has a larger set of cells to infect. “The current hypothesis is that perhaps there should be seven or even 10 times as many cells available for the virus if it crosses the endosomes and does not depend on TMPRSS2,” says Wendy Barclay, virologist at Imperial College London, whose team, among others, detected the new entry route , which they described in a pre-printed study.

Second, while the Delta variant often dived to infect lung cells rich in TMPRSS2, Omicron replicated rapidly in the airways above the lungs, which probably helped it spread from person to person to person. “We may be seeing a change in the upper respiratory tract, which promotes the spread of the virus through coughing, sneezing and so on,” explained Joe Grove, virologist at the University of Glasgow and co-author of a prepress that also detected the change of entry.

4-He lowered his defenses: A fourth final change to Ómicron did not help make the variant more infectious, unlike the first three. Instead, the alteration created a surprising weakness, which made the variant more vulnerable to a part of our body's defenses known as the innate immune system. Scientists examined Omicron and Delta's responses to interferons, small proteins that act like flares on roads and alert innate immune cells to invaders. Delta was a master at mastering the interferon response, but Omicron was terrible. In fact, it activated interferon signaling.

Researchers do not yet know how this change came about. At least 11 of the 26 coronavirus proteins interact with the interferon system, and many of them were mutated in Ómicron. But even without knowing the exact mechanism, scientists can see signs of the consequences of this change.

Because the lungs have a more pronounced interferon response than the upper respiratory tract, Omicron's vulnerability to that reaction may have prevented it from spreading to the deeper organ. “It makes biological sense from what we see,” said Dr. Martin Michaelis, a biologist at the University of Kent in England, who analyzed how Ómicron interacts with interferon in an article published in Cell Research. “Omicron seems to be less able to penetrate further into the body and lungs to cause serious illness.”

Although Ómicron's impact on our entire population was not mild, it caused a huge increase in hospitalizations and deaths and a record number of hospitalized children, the variant did appear to cause a less serious disease in some infected people, as well as in animal models. However, those who were not vaccinated or had other risk factors still had a much higher risk of serious illness and death.

Future variants, if and when they appear, may have other modifications to their structures and abilities. “I'm not sure we can rest on our laurels and say this is all over,” Barclay says. As infections continue to spread and evolve among many populations around the world, the virus will present more forms of transmission, including some that scientists have not yet thought of.

Infographic: Marcelo Regalado

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