Early indications from South Africa and the United Kingdom signal that the rapidly spreading Omicron variant of coronavirus SARS-CoV-2 is less dangerous than its predecessor Delta. Now, a number of laboratory studies provide a tempting explanation for the difference: Omicron does not infect cells deep in the lungs as easily as it does them in the upper respiratory tract.
“It’s a very attractive observation that may explain what we see in patients,” said Melanie Ott, a virologist at the Gladstone Institute of Virology in San Francisco, California, who was not involved in the research. But she adds that Omicron’s hyper-transferability means hospitals are filling up fast – despite any drop in the severity of the disease it causes.
Authorities in South Africa announced on December 30 that the country had passed its Omicron summit without a large number of deaths. And a December 31, UK government report said people in the UK infected with Omicron were about half as likely to require hospitalization or emergency treatment as those infected with Delta.
However, the number of people who have acquired immune protection against COVID-19 through vaccination, infection, or both has grown over time, making it difficult to determine whether Omicron itself causes milder disease than previous variants. To get answers, researchers have turned to animals and cells in laboratory dishes.
Michael Diamond, a virologist at Washington University in St. Louis, Missouri, and his colleagues infected hamsters and mice with Omicron and other variants to track disease progression. The differences were staggering: after a few days, the concentration of virus in the lungs of animals infected with Omicron was at least ten times lower than in rodents infected with other variants.1. Other teams have also noted that compared to previous variants, Omicron is found in reduced levels in lung tissue2,3.
Diamond says he was particularly shocked to see that the Omicron-infected animals almost kept their body weight while the others quickly lost weight – a sign that their infections were causing serious illness. “Every strain of SARS-CoV-2 has very easily infected hamsters, to high levels,” he says, “and it’s clear that this is different for hamsters.” The lungs are where the coronavirus does much of its damage, and lung infection can trigger an inflammatory immune response that ravages both infected and uninfected cells, leading to tissue formation and oxygen deficiency. Fewer infected lung cells can mean milder disease.
Another group found that Omicron is much less successful than previous variants in infecting lung cells and miniature lung models called organoids4. These experiments also identified a plausible player in the difference: a protein called TMPRSS2, which protrudes from the surface of many cells in the lungs and other organs, but is especially absent from the surface of most nose and throat cells.
Previous variants have utilized this protein to infect cells, but the researchers noted that Omicron does not bind as well to TMPRSS2. Instead, it prefers to enter cells by fusing directly with their membranes, a discovery rendered by other teams5,6.
Upper airways are preferred
Difficulty getting into lung cells may help explain why Omicron performs better in the upper respiratory tract than in the lungs, says Ravindra Gupta, a virologist at the University of Cambridge, UK, who co-authored one of the TMPRSS2 studies.4. This theory could also explain why, according to some estimates, Omicron is almost as transferable as measles, which is the benchmark for high transferability, Diamond says. If the variant gets stuck in the upper respiratory tract, viral particles can find it easy to take a trip on material expelled from the nose and mouth, allowing the virus to find new hosts, Gupta says. Other data provide direct evidence that Omicron replicates more easily in the upper respiratory tract than in the lungs2,5.
Recent results may mean that “the virus establishes a very local infection in the upper respiratory tract and has less chance of going into chaos in the lungs,” says Ott. That would be welcome news – but a host’s immune response plays an important role in the severity of the disease, and scientists need more clinical data if they are to understand how Omicron’s basic biology affects its disease progression in humans.
Omicron’s course of infection can also have consequences for children, says Audrey John, a specialist in pediatric infectious diseases at the Children’s Hospital of Philadelphia in Pennsylvania. Young children have relatively small nasal passages, and babies only breathe through the nose. Such factors can make upper respiratory tract diseases more serious for children than for adults, John says. However, she adds that she has not seen data suggesting an increase in the number of young children hospitalized due to ticks and other conditions that could indicate a serious upper respiratory tract infection.
Although there is still much to learn about the new variant, Gupta says the fears raised in late November by the many mutations in Omicron’s genome have not been fully confirmed. He says the first alarm offers a warning story: it is difficult to predict how a virus will infect organisms from its genetic sequence alone.