May 2022, ScientificAmerican.com 61stant: the virus relies on a protein on the
surface of human cells called TMPRSS2
(pronounced “tempress two”) to help it
break through the cell membrane. But
Omicron did not use TMPRSS2. It took a
wholly different route into the cell. In -
stead of breaking down the front door, it
slipped in through the side.
While other variants require both the
ACE2 and TMPRSS2 proteins to inject
their genome into a cell, Omicron bound
only to ACE2. Then it was engulfed in a
hollow bubble called an endosome. The
bubble drifted into the cell, where the
virus broke out and began a takeover.
Scientists speculate that Omicron
gained two possible advantages this way.
First, many cells do not have TMPRSS2
on their exterior, so if the virus does not
need the surface protein, it has a wider
buffet of cells to infect. “The current
hypothesis is that there should be maybe
seven or even 10 times more cells avail-
able to the virus if it goes through endo-
somes and isn’t reliant on TMPRSS2,”
says Wendy Barclay, a virologist at Impe-
rial College London, whose team, among
others, detected the new entry pathway,
which they described in a preprint.
Second, while the Delta variant often
dove down to infect TMPRSS2-rich lung
cells, Omicron replicated quickly in the
airway above the lungs, which probably
helped it spread from person to person.
“We may be seeing a switch to the upper
airway, which is promoting spread of the virus through cough-
ing, sneezing, and such,” says Joe Grove, a virologist at the Uni-
versity of Glasgow and co-author of a preprint that also detected
the entry change.
It dropped its defenses. A final, fourth change to Omicron
did not help to make the variant more infectious, unlike the first
three. Instead the alteration created a surprising weakness, ren-
dering the variant more vulnerable to a part of our bodily
defenses known as the innate immune system.
Scientists examined the responses from Omicron and Delta
to interferons, small proteins that act like highway flares and
alert innate immune cells to invaders. Delta was masterful at
subduing the interferon response—but Omicron was terrible. It
actually activated interferon signaling.
Researchers do not yet know how this change came about. At
least 11 of the coronavirus’s 26 proteins interact with the inter-
feron system, and many of those were mutated in Omicron. But
even without knowing the exact mechanism, scientists can see
hints of the consequences of this change.
Because the lungs have a more pronounced interferon re -
sponse than the upper respiratory tract does, Omicron’s vulner-
ability to that reaction may have prevented it from spreading to
the deeper organ. “It makes biological sense for what we see,”
says Martin Michaelis, a biologist at the University of Kent in
England, who analyzed how Omicron interacts with interferon
in a paper published in Cell Research. “Omicron seems to be less
capable of making it further into the body and into the lungs to
cause severe disease.”
Although Omicron’s impact on our whole population was not
mild—it led to a giant surge in hospitalizations and deaths and
a record number of hospitalized children—the variant did appear
to cause less severe disease in some infected people, as well as
in animal models. Those who were unvaccinated or had other
risk factors were still at greatly heightened risk for severe illness
and death, however.
Future variants, if and when they appear, may have yet other
modifications to their structures and abilities. “I’m not confident
that we can rest on our laurels and say this is all over,” Barclay
says. With infections continuing to spread and evolve among
many populations around the world, the virus is going to come
up with more ways to transmit—including ones that scientists
haven’t even thought of yet.FROM OUR ARCHIVES
Data Captured COVID’s Uneven Toll. Amanda Montañez et al.; March 2022.
scientificamerican.com/magazine/saOther variants infect cells in
the lungs and replicate thereOmicron readily infects cells
and replicates in the airway
above the lungsACE2 TMPRSS2Older variant OmicronViral genome EndosomeACE2Alternative Cell Entry
Older variants of the virus used two proteins, called ACE2 and TMPRSS2, to get
inside a cell. Those variants fused with the cell membrane and injected viral genetic
material into the cell. Omicron needs only ACE2 to get inside, making cells without
TMPRSS2 available for infection. The variant is encapsulated in a bubble called an
endosome, drifts into cells and then breaks out.