Scientists are just beginning to untangle omicron’s mysteries, but the locations of mutations in key parts of the spike provide some clues.
A look at the spike
Every spike on a coronavirus’s surface is made of three identical proteins twisted together, making it look a little like a head of broccoli with three stalks.
Each stalk has three vital regions — the receptor binding domain (RBD), the N-terminal domain (NTD) and the furin cleavage site (FCS) — and most of omicron’s mutations are in these three areas.
A key to transmissibility: the receptor binding domain
Amino acids in this area attach to a cell’s receptor like a key in a lock, opening the cell so the virus can enter.
When scientists first peered at omicron’s genetic code, they knew that some of the 15 mutations in this area of the spike would make the virus’s connection to the cell stronger, and they feared that others might strengthen it even more. A tightened connection would allow omicron to spread more easily than its predecessors.
Early data bears that out: Omicron is rapidly spreading in many places, and various models indicate that it may be two to three times more transmissible than the delta variant, which continues to surge through the United States and much of the world.
“There’s no question that this will be more transmissible than delta,” said Mark Zeller, a staff scientist at Scripps Research whose team sequences viruses.
Part of the problem is that in addition to being the location where the virus binds to cells, the domain is ground zero in our immune system’s attack on the virus.
Specialized fighting forces called neutralizing antibodies try to latch on here to block the spike from attaching to cell receptors. (Monoclonal antibody treatments are an example of neutralizing antibodies.)
Those antibodies developed to attack the spikes of a previous version of the virus, which were largely similar to each other. Antibodies may find it more difficult to attach to the vastly different omicron spike.
Notable mutations in this area
If the receptor binding domain were a catcher’s mitt, 10 mutations are right in the pocket. Amino acids in this sweet spot interact most directly with the cell’s receptors.
One of these mutations is N501Y, which omicron shares with the alpha, beta and gamma variants. It helps the virus cling more tightly to cell receptors and muscle out antibodies. How it will work in concert with omicron’s many new mutations around it is not yet known.
Beta and gamma share the E484K mutation, which appears to thwart certain neutralizing antibodies by changing the shape of their target. Omicron has a different amino acid in that spot, and it has changed other immune system targets as well. So the question is whether, and how well, antibodies will still recognize the enemy. Fortunately, at least one type of monoclonal antibody called sotrovimab does not seem fooled by the new variant.
A key to immunity: the N-terminal domain
Scientists are not sure exactly what this area’s function is, said Tulane microbiologist Robert F. Garry, an expert on the virus’s anatomy. It may help viruses attach to cells in some way.
But it is clear that antibodies — both the kind triggered by vaccines and the kind triggered by previous infection — target this area.
Notable mutations in this area
In omicron, the N-terminal domain has been extensively overhauled, said Zeller. Four amino acids were swapped out, six total were deleted from three locations and three new ones were added together in one spot.
Scientists suspect this extensive remodeling means antibodies will bind less efficiently, so they will be less effective at stopping the virus from infecting new cells.
The first lab study of omicron indicated that it may indeed evade quite a bit of antibody protection. Early data also shows that people who received boosters on top of full vaccination still remain largely protected from the most severe effects of covid, although it will vary greatly from person to person.
A key to severe illness: the furin cleavage site
Once inside a cell, the coronavirus causes an infection by turning the cell’s machinery into a tiny factory that churns out new copies of the virus.
As new viruses leave the factory, the human enzyme furin acts like a trigger, activating them by snipping their spikes as they head out the door. The place on the spike’s stalk where that snip occurs is called the furin cleavage site.
What happens after that snip is complicated and involves the loose ends helping to fuse cell membranes together. But the upshot is that the virus is able to slip more easily from one cell to the next without exposing itself to antibodies.
Not all viruses have furin cleavage sites, but ones that do can often spread more easily into a wider range of tissues, Garry said. It is probably one of the major reasons SARS-CoV-2, the virus that causes covid, is able to penetrate so deeply into the lungs and make some people extremely sick.
Notable mutations in this area
A cluster of mutations near the furin cleavage site may let omicron more easily slide into cells.
Garry said alpha beefed up its site over the original virus’s, and delta’s site is better than alpha’s. Many studies have pegged the mutation at position 681 as a reason delta spreads so efficiently.
Omicron’s mutation at that position is identical to alpha’s, not delta’s, which would appear to be a step backward. However, omicron has two unique mutations nearby. No one knows whether the combination of the three will make omicron’s site better, worse, or about the same as delta’s.
Early data suggests omicron may cause milder illness than delta in most people — an enormous silver lining in the dark cloud of a more highly transmissible variant.
Not every mutation improves a virus. In fact, most either harm the virus or have little effect. But a new variant does not begin to elbow out others unless some mutation or combination of them makes it superior to its predecessors, Garry said. “It’s either making the virus replicate better, transmit better or resist the immune system better.”
So far, he said, omicron appears to be at least two for three.
About this story: Most of the information on the spike protein, its anatomy and mutations came from Robert F. Garry at Tulane and Mark Zeller of the Andersen Lab at Scripps Research. Additional sources were CoVariants, GISAID, Nextstrain, and ViralZone, which is part of the SIB Swiss Institute of Bioinformatics.
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